Summary: Serpin (serine protease inhibitor)
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Serpin Edit Wikipedia article
|Serpin (serine protease inhibitor)|
|Symbol||Serpin, SERPIN (root symbol of family)|
|SCOP2||1hle / SCOPe / SUPFAM|
Serpins are a superfamily of proteins with similar structures that were first identified for their protease inhibition activity and are found in all kingdoms of life. The acronym serpin was originally coined because the first serpins to be identified act on chymotrypsin-like serine proteases (serine protease inhibitors). They are notable for their unusual mechanism of action, in which they irreversibly inhibit their target protease by undergoing a large conformational change to disrupt its active site. This contrasts with the more common competitive mechanism for protease inhibitors that bind to and block access to the protease active site.
Protease inhibition by serpins controls an array of biological processes, including coagulation and inflammation, and consequently these proteins are the target of medical research. Their unique conformational change also makes them of interest to the structural biology and protein folding research communities. The conformational-change mechanism confers certain advantages, but it also has drawbacks: serpins are vulnerable to mutations that can result in serpinopathies such as protein misfolding and the formation of inactive long-chain polymers. Serpin polymerisation not only reduces the amount of active inhibitor, but also leads to accumulation of the polymers, causing cell death and organ failure.
Although most serpins control proteolytic cascades, some proteins with a serpin structure are not enzyme inhibitors, but instead perform diverse functions such as storage (as in egg whiteâ€”ovalbumin), transport as in hormone carriage proteins (thyroxine-binding globulin, cortisol-binding globulin) and molecular chaperoning (HSP47). The term serpin is used to describe these members as well, despite their non-inhibitory function, since they are evolutionarily related.
Protease inhibitory activity in blood plasma was first reported in the late 1800s, but it was not until the 1950s that the serpins antithrombin and alpha 1-antitrypsin were isolated. Initial research focused on their role in human disease: alpha 1-antitrypsin deficiency is one of the most common genetic disorders, causing emphysema, and antithrombin deficiency results in thrombosis.
In the 1980s, it became clear that these inhibitors were part of superfamily of related proteins that included both protease inhibitors (e.g. alpha 1-antitrypsin) and non-inhibitory members (e.g. ovalbumin). The name "serpin" was coined based on the most common activity of the superfamily (serine protease inhibitors). Around the same time, the first structures were solved for serpin proteins (first in the relaxed, and later in the stressed conformation). The structures indicated that the inhibitory mechanism involved an unusual conformational change and prompted the subsequent structural focus of serpin studies.
Over 1000Â serpins have now been identified, including 36Â human proteins, as well as molecules in all kingdoms of lifeâ€”animals, plants, fungi, bacteria, and archaeaâ€”and some viruses. In the 2000s, a systematic nomenclature was introduced in order to categorise members of the serpin superfamily based on their evolutionary relationships. Serpins are therefore the largest and most diverse superfamily of protease inhibitors.
Most serpins are protease inhibitors, targeting extracellular, chymotrypsin-like serine proteases. These proteases possess a nucleophilic serine residue in a catalytic triad in their active site. Examples include thrombin, trypsin, and human neutrophil elastase. Serpins act as irreversible, suicide inhibitors by trapping an intermediate of the protease's catalytic mechanism.
Some serpins inhibit other protease classes, typically cysteine proteases, and are termed "cross-class inhibitors". These enzymes differ from serine proteases in that they use a nucleophilic cysteine residue, rather than a serine, in their active site. Nonetheless, the enzymatic chemistry is similar, and the mechanism of inhibition by serpins is the same for both classes of protease. Examples of cross-class inhibitory serpins include serpin B4 a squamous cell carcinoma antigenÂ 1 (SCCA-1) and the avian serpin myeloid and erythroid nuclear termination stage-specific protein (MENT), which both inhibit papain-like cysteine proteases.
Biological function and localization
Approximately two-thirds of human serpins perform extracellular roles, inhibiting proteases in the bloodstream in order to modulate their activities. For example, extracellular serpins regulate the proteolytic cascades central to blood clotting (antithrombin), the inflammatory and immune responses (antitrypsin, antichymotrypsin, and C1-inhibitor) and tissue remodelling (PAI-1). By inhibiting signalling cascade proteases, they can also affect development. The table of human serpins (below) provides examples of the range of functions performed by human serpin, as well as some of the diseases that result from serpin deficiency.
The protease targets of intracellular inhibitory serpins have been difficult to identify, since many of these molecules appear to perform overlapping roles. Further, many human serpins lack precise functional equivalents in model organisms such as the mouse. Nevertheless, an important function of intracellular serpins may be to protect against the inappropriate activity of proteases inside the cell. For example, one of the best-characterised human intracellular serpins is Serpin B9, which inhibits the cytotoxic granule protease granzyme B. In doing so, Serpin B9 may protect against inadvertent release of granzyme B and premature or unwanted activation of cell death pathways.
Some viruses use serpins to disrupt protease functions in their host. The cowpox viral serpin CrmA (cytokine response modifier A) is used in order to avoid inflammatory and apoptotic responses of infected host cells. CrmA increases infectivity by suppressing its host's inflammatory response through inhibition of IL-1 and IL-18 processing by the cysteine protease caspase-1. In eukaryotes, a plant serpin inhibits both metacaspases and a papain-like cysteine protease.
Non-inhibitory extracellular serpins also perform a wide array of important roles. Thyroxine-binding globulin and transcortin transport the hormones thyroxine and cortisol, respectively. The non-inhibitory serpin ovalbumin is the most abundant protein in egg white. Its exact function is unknown, but it is thought to be a storage protein for the developing foetus. Heat shock serpin 47 is a chaperone, essential for proper folding of collagen. It acts by stabilising collagen's triple helix whilst it is being processed in the endoplasmic reticulum.
Some serpins are both protease inhibitors and perform additional roles. For example, the nuclear cysteine protease inhibitor MENT, in birds also acts as a chromatin remodelling molecule in a bird's red blood cells.
All serpins share a common structure (or fold), despite their varied functions. All typically have three Î²-sheets (named A, B and C) and eight or nine Î±-helices (named hAâ€“hI). The most significant regions to serpin function are the A-sheet and the reactive centre loop (RCL). The A-sheet includes two Î²-strands that are in a parallel orientation with a region between them called the 'shutter', and upper region called the 'breach'. The RCL forms the initial interaction with the target protease in inhibitory molecules. Structures have been solved showing the RCL either fully exposed or partially inserted into the A-sheet, and serpins are thought to be in dynamic equilibrium between these two states. The RCL also only makes temporary interactions with the rest of the structure, and is therefore highly flexible and exposed to the solvent.
The serpin structures that have been determined cover several different conformations, which has been necessary for the understanding of their multiple-step mechanism of action. Structural biology has therefore played a central role in the understanding of serpin function and biology.
Conformational change and inhibitory mechanism
Inhibitory serpins do not inhibit their target proteases by the typical competitive (lock-and-key) mechanism used by most small protease inhibitors (e.g. Kunitz-type inhibitors). Instead, serpins use an unusual conformational change, which disrupts the structure of the protease and prevents it from completing catalysis. The conformational change involves the RCL moving to the opposite end of the protein and inserting into Î²-sheet A, forming an extra antiparallel Î²-strand. This converts the serpin from a stressed state, to a lower-energy relaxed state (S to R transition).
Serine and cysteine proteases catalyse peptide bond cleavage by a two-step process. Initially, the catalytic residue of the active site triad performs a nucleophilic attack on the peptide bond of the substrate. This releases the new N-terminus and forms a covalent ester-bond between the enzyme and the substrate. This covalent complex between enzyme and substrate is called an acyl-enzyme intermediate. For standard substrates, the ester bond is hydrolysed and the new C-terminus is released to complete catalysis. However, when a serpin is cleaved by a protease, it rapidly undergoes the S to R transition before the acyl-enzyme intermediate is hydrolysed. The efficiency of inhibition depends on fact that the relative kinetic rate of the conformational change is several orders of magnitude faster than hydrolysis by the protease.
Since the RCL is still covalently attached to the protease via the ester bond, the S to R transition pulls protease from the top to the bottom of the serpin and distorts the catalytic triad. The distorted protease can only hydrolyse the acyl enzyme intermediate extremely slowly and so the protease remains covalently attached for days to weeks. Serpins are classed as irreversible inhibitors and as suicide inhibitors since each serpin protein permanently inactivates a single protease, and can only function once.
The conformational mobility of serpins provides a key advantage over static lock-and-key protease inhibitors. In particular, the function of inhibitory serpins can be regulated by allosteric interactions with specific cofactors. The X-ray crystal structures of antithrombin, heparin cofactor II, MENT and murine antichymotrypsin reveal that these serpins adopt a conformation wherein the first two amino acids of the RCL are inserted into the top of the A Î²-sheet. The partially inserted conformation is important because co-factors are able to conformationally switch certain partially inserted serpins into a fully expelled form. This conformational rearrangement makes the serpin a more effective inhibitor.
The archetypal example of this situation is antithrombin, which circulates in plasma in a partially inserted relatively inactive state. The primary specificity determining residue (the P1 arginine) points toward the body of the serpin and is unavailable to the protease. Upon binding a high-affinity pentasaccharide sequence within long-chain heparin, antithrombin undergoes a conformational change, RCL expulsion, and exposure of the P1 arginine. The heparin pentasaccharide-bound form of antithrombin is, thus, a more effective inhibitor of thrombin and factor Xa. Furthermore, both of these coagulation proteases also contain binding sites (called exosites) for heparin. Heparin, therefore, also acts as a template for binding of both protease and serpin, further dramatically accelerating the interaction between the two parties. After the initial interaction, the final serpin complex is formed and the heparin moiety is released. This interaction is physiologically important. For example, after injury to the blood vessel wall, heparin is exposed, and antithrombin is activated to control the clotting response. Understanding of the molecular basis of this interaction enabled the development of Fondaparinux, a synthetic form of Heparin pentasaccharide used as an anti-clotting drug.
Certain serpins spontaneously undergo the S to R transition without having been cleaved by a protease, to form a conformation termed the latent state. Latent serpins are unable to interact with proteases and so are no longer protease inhibitors. The conformational change to latency is not exactly the same as the S to R transition of a cleaved serpin. Since the RCL is still intact, the first strand of the C-sheet has to peel off to allow full RCL insertion.
Regulation of the latency transition can act as a control mechanism in some serpins, such as PAI-1. Although PAI-1 is produced in the inhibitory S conformation, it "auto-inactivates" by changing to the latent state unless it is bound to the cofactor vitronectin. Similarly, antithrombin can also spontaneously convert to the latent state, as an additional modulation mechanism to its allosteric activation by heparin. Finally, the N-terminus of tengpin, a serpin from Thermoanaerobacter tengcongensis, is required to lock the molecule in the native inhibitory state. Disruption of interactions made by the N-terminal region results in spontaneous conformational change of this serpin to the latent conformation.
Conformational change in non-inhibitory functions
Certain non-inhibitory serpins also use the serpin conformational change as part of their function. For example, the native (S) form of thyroxine-binding globulin has high affinity for thyroxine, whereas the cleaved (R) form has low affinity. Similarly, transcortin has higher affinity for cortisol when in its native (S) state, than its cleaved (R) state. Thus, in these serpins, RCL cleavage and the S to R transition has been commandeered to allow for ligand release, rather than protease inhibition.
In some serpins, the S to R transition can activate cell signalling events. In these cases, a serpin that has formed a complex with its target protease, is then recognised by a receptor. The binding event then leads to downstream signalling by the receptor. The S to R transition is therefore used to alert cells to the presence of protease activity. This differs from the usual mechanism whereby serpins affect signalling simply by inhibiting proteases involved in a signalling cascade.
When a serpin inhibits a target protease, it forms a permanent complex, which needs to be disposed of. For extracellular serpins, the final serpin-enzyme complexes are rapidly cleared from circulation. One mechanism by which this occurs in mammals is via the low-density lipoprotein receptor-related protein (LRP), which binds to inhibitory complexes made by antithrombin, PA1-1, and neuroserpin, causing cellular uptake. Similarly, the Drosophila serpin, necrotic, is degraded in the lysosome after being trafficked into the cell by the Lipophorin Receptor-1 (homologous to the mammalian LDL receptor family).
Disease and serpinopathies
Serpins are involved in a wide array of physiological functions, and so mutations in genes encoding them can cause a range of diseases. Mutations that change the activity, specificity or aggregation properties of serpins all affect how they function. The majority of serpin-related diseases are the result of serpin polymerisation into aggregates, though several other types of disease-linked mutations also occur. The disorder alpha-1 antitrypsin deficiency is one of the most common hereditary diseases.
Inactivity or absence
Since the stressed serpin fold is high-energy, mutations can cause them to incorrectly change into their lower-energy conformations (e.g. relaxed or latent) before they have correctly performed their inhibitory role.
Mutations that affect the rate or the extent of RCL insertion into the A-sheet can cause the serpin to undergo its S to R conformational change before having engaged a protease. Since a serpin can only make this conformational change once, the resulting misfired serpin is inactive and unable to properly control its target protease. Similarly, mutations that promote inappropriate transition to the monomeric latent state cause disease by reducing the amount of active inhibitory serpin. For example, the disease-linked antithrombin variants wibble and wobble, both promote formation of the latent state.
The structure of the disease-linked mutant of antichymotrypsin (L55P) revealed another, inactive "Î´-conformation". In the Î´-conformation, four residues of the RCL are inserted into the top of Î²-sheet A. The bottom half of the sheet is filled as a result of one of the Î±-helices (the F-helix) partially switching to a Î²-strand conformation, completing the Î²-sheet hydrogen bonding. It is unclear whether other serpins can adopt this conformer, and whether this conformation has a functional role, but it is speculated that the Î´-conformation may be adopted by Thyroxine-binding globulin during thyroxine release. The non-inhibitory proteins related to serpins can also cause diseases when mutated. For example, mutations in SERPINF1 cause osteogenesis imperfecta type VI in humans.
In the absence of a required serpin, the protease that it normally would regulate is over-active, leading to pathologies. Consequently, simple deficiency of a serpin (e.g. a null mutation) can result in disease. Gene knockouts, particularly in mice, are used experimentally to determine the normal functions of serpins by the effect of their absence.
In some rare cases, a single amino acid change in a serpin's RCL alters its specificity to target the wrong protease. For example, the Antitrypsin-Pittsburgh mutation (M358R) causes the Î±1-antitrypsin serpin to inhibit thrombin, causing a bleeding disorder.
Polymerisation and aggregation
The majority of serpin diseases are due to protein aggregation and are termed "serpinopathies". Serpins are vulnerable to disease-causing mutations that promote formation of misfolded polymers due to their inherently unstable structures. Well-characterised serpinopathies include Î±1-antitrypsin deficiency (alpha-1), which may cause familial emphysema, and sometimes liver cirrhosis, certain familial forms of thrombosis related to antithrombin deficiency, typesÂ 1 and 2 hereditary angioedema (HAE) related to deficiency of C1-inhibitor, and familial encephalopathy with neuroserpin inclusion bodies (FENIB; a rare type of dementia caused by neuroserpin polymerisation).
Each monomer of the serpin aggregate exists in the inactive, relaxed conformation (with the RCL inserted into the A-sheet). The polymers are therefore hyperstable to temperature and unable to inhibit proteases. Serpinopathies therefore cause pathologies similarly to other proteopathies (e.g. prion diseases) via two main mechanisms. First, the lack of active serpin results in uncontrolled protease activity and tissue destruction. Second, the hyperstable polymers themselves clog up the endoplasmic reticulum of cells that synthesize serpins, eventually resulting in cell death and tissue damage. In the case of antitrypsin deficiency, antitrypsin polymers cause the death of liver cells, sometimes resulting in liver damage and cirrhosis. Within the cell, serpin polymers are slowly removed via degradation in the endoplasmic reticulum. However, the details of how serpin polymers cause cell death remains to be fully understood.
Physiological serpin polymers are thought to form via domain swapping events, where a segment of one serpin protein inserts into another. Domain-swaps occur when mutations or environmental factors interfere with the final stages of serpin folding to the native state, causing high-energy intermediates to misfold. Both dimer and trimer domain-swap structures have been solved. In the dimer (of antithrombin), the RCL and part of the A-sheet incorporates into the A-sheet of another serpin molecule. The domain-swapped trimer (of antitrypsin) forms via the exchange of an entirely different region of the structure, the B-sheet (with each molecule's RCL inserted into its own A-sheet). It has also been proposed that serpins may form domain-swaps by inserting the RCL of one protein into the A-sheet of another (A-sheet polymerisation). These domain-swapped dimer and trimer structures are thought to be the building blocks of the disease-causing polymer aggregates, but the exact mechanism is still unclear.
Several therapeutic approaches are in use or under investigation to treat the most common serpinopathy: antitrypsin deficiency. Antitrypsin augmentation therapy is approved for severe antitrypsin deficiency-related emphysema. In this therapy, antitrypsin is purified from the plasma of blood donors and administered intravenously (first marketed as Prolastin). To treat severe antitrypsin deficiency-related disease, lung and liver transplantation has proven effective. In animal models, gene targeting in induced pluripotent stem cells has been successfully used to correct an antitrypsin polymerisation defect and to restore the ability of the mammalian liver to secrete active antitrypsin. Small molecules have also been developed that block antitrypsin polymerisation in vitro.
Serpins are the most widely distributed and largest superfamily of protease inhibitors. They were initially believed to be restricted to eukaryote organisms, but have since been found in bacteria, archaea and some viruses. It remains unclear whether prokaryote genes are the descendants of an ancestral prokaryotic serpin or the product of horizontal gene transfer from eukaryotes. Most intracellular serpins belong to a single phylogenetic clade, whether they come from plants or animals, indicating that the intracellular and extracellular serpins may have diverged before the plants and animals. Exceptions include the intracellular heat shock serpin HSP47, which is a chaperone essential for proper folding of collagen, and cycles between the cis-Golgi and the endoplasmic reticulum.
Protease-inhibition is thought to be the ancestral function, with non-inhibitory members the results of evolutionary neofunctionalisation of the structure. The S to R conformational change has also been adapted by some binding serpins to regulate affinity for their targets.
The human genome encodes 16Â serpin clades, termed serpinA through serpinP, including 29Â inhibitory and 7Â non-inhibitory serpin proteins. The human serpin naming system is based upon a phylogenetic analysis of approximately 500Â serpins from 2001, with proteins named serpinXY, where X is the clade of the protein and Y the number of the protein within that clade. The functions of human serpins have been determined by a combination of biochemical studies, human genetic disorders, and knockout mouse models.
|Gene name||Common Name||Localisation||Function / Activity||Effect of deficiency||Human disease||Chromosomal location||Protein structure|
|SERPINA1||Î±1-antitrypsin||Extracellular||Inhibitor of human neutrophil elastase. The C-terminal fragment of cleaved SERPINA1 may inhibit HIV-1 infection.||Deficiency results in emphysema, polymerisation results in cirrhosis (serpinopathy).||14q32.1||â€‹, â€‹, â€‹|
|SERPINA2||Antitrypsin-related protein||Extracellular||Possible pseudogene.||14q32.1|
|SERPINA3||Î±1-antichymotrypsin||Extracellular||Inhibitor of cathepsin G. Additional roles in chromatin condensation in hepatic cells.||Mis-regulation results in Alzheimer's disease (serpinopathy).||14q32.1||â€‹, â€‹|
|SERPINA4||Kallistatin||Extracellular||Inhibitor of kallikrein, regulator of vascular function.||Depletion in hypertensive rats exacerbates renal and cardiovascular injury.||14q32.1|
|SERPINA5||Protein C inhibitor||Extracellular||Inhibitor of active protein C. Intracellular role in preventing phagocytosis of bacteria.||Knockout in male mice causes infertility. Accumulation occurs in chronic active plaques in multiple sclerosis.||14q32.1||â€‹, â€‹|
|SERPINA6||Transcortin||Extracellular||Non-inhibitory. Cortisol binding.||Deficiency associated with chronic fatigue.||14q32.1||â€‹, â€‹, â€‹|
|SERPINA7||Thyroxine-binding globulin||Extracellular||Non-inhibitory. Thyroxine binding.||Deficiency causes hypothyroidism.||Xq22.2||â€‹, â€‹, â€‹|
|SERPINA8||Angiotensinogen||Extracellular||Non-inhibitory, cleavage by renin results in release of angiotensin I.||Knockout in mice causes hypotension.||Variants linked to hypertension.||1q42-q43||â€‹, â€‹, â€‹, â€‹, â€‹, â€‹, â€‹|
|SERPINA9||Centerin / GCET1||Extracellular||Inhibitory, maintenance of naive B cells.||Strongly expressed in most B-cell lymphomas.||14q32.1|
|SERPINA10||Protein Z-related protease inhibitor||Extracellular||Binds protein Z and inactivates factor Xa and factor XIa.||14q32.1||â€‹, â€‹|
|SERPINA12||Vaspin||Extracellular||Inhibitor of Kallikrein-7. Insulin-sensitizing adipocytokine.||High plasma levels associated with type II diabetes.||14q32.1||â€‹|
|SERPINB1||Monocyte neutrophil elastase inhibitor||Intracellular||Inhibitor of neutrophil elastase.||Knockout in mice causes neutrophil survival defect and immune deficiency.||6p25||â€‹|
|SERPINB2||Plasminogen activator inhibitor-2||Intracellular/extracellular||Inhibitor of extracellular uPA. Intracellular function unclear, but may protect against viral infection.||Deficiency in mice reduces immune response to nematode infection. Knockout in mice causes no obvious phenotype.||18q21.3||â€‹|
|SERPINB3||Squamous cell carcinoma antigen-1 (SCCA-1)||Intracellular||Inhibitor of papain-like cysteine proteases and cathepsins K, L and S.||Knockout in mice of Serpinb3a (the murine homolog of both human SERPINB3 and SERPINB4) have reduced mucus production in a murine model of asthma.||18q21.3||â€‹|
|SERPINB4||Squamous cell carcinoma antigen-2 (SCCA-2)||Intracellular||Inhibitor of chymotrypsin-like serine proteases, cathepsin G and chymase.||Knockout in mice of Serpinb3a (the murine homolog of both human SERPINB3 and SERPINB4) have reduced mucus production in a murine model of asthma.||18q21.3|
|SERPINB5||Maspin||Intracellular||Non-inhibitory, function unclear (see also maspin)||Knockout in mice originally reported as lethal, but subsequently shown to have no obvious phenotype. Expression may be a prognostic indicator that reflects expression of a neighbouring tumour suppressor gene (the phosphatase PHLPP1).||18q21.3||â€‹|
|SERPINB6||PI-6||Intracellular||Inhibitor of cathepsin G.||Knockout in mice causes hearing loss and mild neutropenia.||Deficiency associated with hearing loss.||6p25|
|SERPINB7||Megsin||Intracellular||Involved in megakaryocyte maturation.||Over-expression in mice causes kidney disease. Knockout in mice does not cause histological abnormalities.||Mutations associated with Nagashima-type Palmoplantar Keratosis.||18q21.3|
|SERPINB8||PI-8||Intracellular||Possible inhibitor of furin.||18q21.3|
|SERPINB9||PI-9||Intracellular||Inhibitor of the cytotoxic granule protease granzyme B.||Knockout in mice causes immune dysfunction.||6p25|
|SERPINB10||Bomapin||Intracellular||Unknown||Knockout in mice causes no obvious phenotype (C57/BL6; lab strain BC069938).||18q21.3|
|SERPINB11||Intracellular||Unknown||Murine Serpinb11 is an active inhibitor whereas the human orthalogue is inactive. Deficiency in ponies is associated with hoof wall separation disease.||18q21.3|
|SERPINB13||Hurpin/Headpin||Intracellular||Inhibitor of papain-like cysteine proteases.||18q21.3|
|SERPINC1||Antithrombin||Extracellular||Inhibitor of coagulation, specifically factor X, factor IX and thrombin.||Knockouts in mice are lethal.||Deficiency results in thrombosis and other clotting disorders (serpinopathy).||1q23-q21||â€‹, â€‹, â€‹, â€‹, â€‹, â€‹|
|SERPIND1||Heparin cofactor II||Extracellular||Inhibitor of thrombin.||Knockouts in mice are lethal.||22q11||â€‹, â€‹|
|SERPINE1||Plasminogen activator inhibitor 1||Extracellular||Inhibitor of thrombin, uPA and TPa.||7q21.3-q22||â€‹, â€‹|
|SERPINE2||Glia derived nexin / Protease nexin I||Extracellular||Inhibitor of uPA and tPA.||Abnormal expression leads to male infertility. Knockout in mice causes epilepsy.||2q33-q35||â€‹|
|SERPINF1||Pigment epithelium derived factor||Extracellular||Non-inhibitory, potent anti-angiogenic molecule. PEDF has been reported to bind the glycosaminoglycan hyaluronan.||Knockout in mice affects the vasculature and mass of the pancreas and the prostate. Promotes Notchâ€“dependent renewal of adult periventricular neural stem cells. Mutations in humans cause osteogenesis imperfecta type VI.||17p13.3||â€‹|
|SERPINF2||Î±2-antiplasmin||Extracellular||Inhibitor of plasmin, inhibitor of fibrinolysis.||Knockouts in mice show increased mice show increased fibrinolysis but no bleeding disorder.||Deficiency causes a rare bleeding disorder.||17pter-p12||â€‹|
|SERPING1||Complement 1-inhibitor||Extracellular||Inhibitor of C1 esterase.||Several polymorphisms associated with macular degeneration and hereditary angeoedema.||11q11-q13.1||â€‹|
|SERPINH1||47 kDa Heat shock protein (HSP47)||Intracellular||Non-inhibitory, molecular chaperone in collagen folding.||Knockouts in mice are lethal.||Mutation in humans causes severe osteogenesis imperfecta.||11p15||â€‹|
|SERPINI1||Neuroserpin||Extracellular||Inhibitor of tPA, uPA and plasmin.||Mutation causes FENIB dementia (serpinopathy).||3q26||â€‹, â€‹, â€‹, â€‹|
|SERPINI2||Pancpin||Extracellular||Unknown||Deficiency in mice causes pancreatic insufficiency via acinar cell loss.||3q26|
Specialised mammalian serpins
Many mammalian serpins have been identified that share no obvious orthology with a human serpin counterpart. Examples include numerous rodent serpins (particularly some of the murine intracellular serpins) as well as the uterine serpins. The term uterine serpin refers to members of the serpin A clade that are encoded by the SERPINA14 gene. Uterine serpins are produced by the endometrium of a restricted group of mammals in the Laurasiatheria clade under the influence of progesterone or estrogen. They are probably not functional proteinase inhibitors and may function during pregnancy to inhibit maternal immune responses against the conceptus or to participate in transplacental transport.
The Drosophila melanogaster genome contains 29Â serpin encoding genes. Amino acid sequence analysis has placed 14 of these serpins in serpin clade Q and three in serpin clade K with the remaining twelve classified as orphan serpins not belonging to any clade. The clade classification system is difficult to use for Drosophila serpins and instead a nomenclature system has been adopted that is based on the position of serpin genes on the Drosophila chromosomes. Thirteen of the Drosophila serpins occur as isolated genes in the genome (including Serpin-27A, see below), with the remaining 16 organised into five gene clusters that occur at chromosome positions 28D (2Â serpins), 42D (5Â serpins), 43A (4Â serpins), 77B (3Â serpins) and 88E (2Â serpins).
Studies on Drosophila serpins reveal that Serpin-27A inhibits the Easter protease (the final protease in the Nudel, Gastrulation Defective, Snake and Easter proteolytic cascade) and thus controls dorsoventral patterning. Easter functions to cleave SpÃ¤tzle (a chemokine-type ligand), which results in toll-mediated signaling. As well as its central role in embryonic patterning, toll signaling is also important for the innate immune response in insects. Accordingly, serpin-27A also functions to control the insect immune response. In Tenebrio molitor (a large beetle), a protein (SPN93) comprising two discrete tandem serpin domains functions to regulate the toll proteolytic cascade.
The genome of the nematode worm C. elegans contains 9Â serpins, all of which lack signal sequences and so are likely intracellular. However, onlyÂ 5 of these serpins appear to function as protease inhibitors. One, SRP-6, performs a protective function and guards against stress-induced calpain-associated lysosomal disruption. Further, SRP-6 inhibits lysosomal cysteine proteases released after lysosomal rupture. Accordingly, worms lacking SRP-6 are sensitive to stress. Most notably, SRP-6 knockout worms die when placed in water (the hypo-osmotic stress lethal phenotype or Osl). It has therefore been suggested that lysosomes play a general and controllable role in determining cell fate.
Plant serpins were amongst the first members of the superfamily that were identified. The serpin barley protein Z is highly abundant in barley grain, and one of the major protein components in beer. The genome of the model plant, Arabidopsis thaliana contain 18Â serpin-like genes, although onlyÂ 8 of these are full-length serpin sequences.
Plant serpins are potent inhibitors of mammalian chymotrypsin-like serine proteases in vitro, the best-studied example being barley serpin Zx (BSZx), which is able to inhibit trypsin and chymotrypsin as well as several blood coagulation factors. However, close relatives of chymotrypsin-like serine proteases are absent in plants. The RCL of several serpins from wheat grain and rye contain poly-Q repeat sequences similar to those present in the prolamin storage proteins of the endosperm. It has therefore been suggested that plant serpins may function to inhibit proteases from insects or microbes that would otherwise digest grain storage proteins. In support of this hypothesis, specific plant serpins have been identified in the phloem sap of pumpkin (CmPS-1) and cucumber plants. Although an inverse correlation between up-regulation of CmPS-1 expression and aphid survival was observed, in vitro feeding experiments revealed that recombinant CmPS-1 did not appear to affect insect survival.
Alternative roles and protease targets for plant serpins have been proposed. The Arabidopsis serpin, AtSerpin1 (At1g47710;  AtSerpin1 also inhibits metacaspase-like proteases in vitro. Two other Arabidopsis serpins, AtSRP2 (At2g14540) and AtSRP3 (At1g64030) appear to be involved in responses to DNA damage.â€‹), mediates set-point control over programmed cell death by targeting the 'Responsive to Desiccation-21' (RD21) papain-like cysteine protease.
A single fungal serpin has been characterized to date: celpin from Piromyces spp. strain E2. Piromyces is a genus of anaerobic fungi found in the gut of ruminants and is important for digesting plant material. Celpin is predicted to be inhibitory and contains two N-terminal dockerin domains in addition to its serpin domain. Dockerins are commonly found in proteins that localise to the fungal cellulosome, a large extracellular multiprotein complex that breaks down cellulose. It is therefore suggested that celpin may protect the cellulosome against plant proteases. Certain bacterial serpins similarly localize to the cellulosome.
Predicted serpin genes are sporadically distributed in prokaryotes. In vitro studies on some of these molecules have revealed that they are able to inhibit proteases, and it is suggested that they function as inhibitors in vivo. Several prokaryote serpins are found in extremophiles. Accordingly, and in contrast to mammalian serpins, these molecules possess elevated resistance to heat denaturation. The precise role of most bacterial serpins remains obscure, although Clostridium thermocellum serpin localises to the cellulosome. It is suggested that the role of cellulosome-associated serpins may be to prevent unwanted protease activity against the cellulosome.
Serpins are also expressed by viruses as a way to evade the host's immune defense. In particular, serpins expressed by pox viruses, including cow pox (vaccinia) and rabbit pox (myxoma), are of interest because of their potential use as novel therapeutics for immune and inflammatory disorders as well as transplant therapy. Serp1 suppresses the TLR-mediated innate immune response and allows indefinite cardiac allograft survival in rats. Crma and Serp2 are both cross-class inhibitors and target both serine (granzyme B; albeit weakly) and cysteine proteases (caspaseÂ 1 and caspaseÂ 8). In comparison to their mammalian counterparts, viral serpins contain significant deletions of elements of secondary structure. Specifically, crmA lacks the D-helix as well as significant portions of the A- and E-helices.
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- Becerra SP, Perez-Mediavilla LA, Weldon JE, Locatelli-Hoops S, Senanayake P, Notari L, Notario V, Hollyfield JG (November 2008). "Pigment epithelium-derived factor binds to hyaluronan. Mapping of a hyaluronan binding site". The Journal of Biological Chemistry. 283 (48): 33310â€“20. doi:10.1074/jbc.M801287200. PMCÂ 2586245. PMIDÂ 18805795.
- Andreu-AgullÃ³ C, Morante-Redolat JM, Delgado AC, FariÃ±as I (December 2009). "Vascular niche factor PEDF modulates Notch-dependent stemness in the adult subependymal zone". Nature Neuroscience. 12 (12): 1514â€“23. doi:10.1038/nn.2437. PMIDÂ 19898467. S2CIDÂ 5332822.
- Wiman B, Collen D (September 1979). "On the mechanism of the reaction between human alpha 2-antiplasmin and plasmin". The Journal of Biological Chemistry. 254 (18): 9291â€“7. doi:10.1016/S0021-9258(19)86843-6. PMIDÂ 158022.
- Lijnen HR, Okada K, Matsuo O, Collen D, Dewerchin M (April 1999). "Alpha2-antiplasmin gene deficiency in mice is associated with enhanced fibrinolytic potential without overt bleeding". Blood. 93 (7): 2274â€“81. doi:10.1182/blood.V93.7.2274. PMIDÂ 10090937.
- Carpenter SL, Mathew P (November 2008). "Alpha2-antiplasmin and its deficiency: fibrinolysis out of balance". Haemophilia. 14 (6): 1250â€“4. doi:10.1111/j.1365-2516.2008.01766.x. PMIDÂ 19141165. S2CIDÂ 205295156.
- Favier R, Aoki N, De Moerloose P (1 July 2001). "Congenital Î±2-plasmin inhibitor deficiencies: a review". British Journal of Haematology. 114 (1): 4â€“10. doi:10.1046/j.1365-2141.2001.02845.x. ISSNÂ 1365-2141. PMIDÂ 11472338. S2CIDÂ 71010865.
- Beinrohr L, Harmat V, DobÃ³ J, LÃ¶rincz Z, GÃ¡l P, ZÃ¡vodszky P (July 2007). "C1 inhibitor serpin domain structure reveals the likely mechanism of heparin potentiation and conformational disease". The Journal of Biological Chemistry. 282 (29): 21100â€“9. doi:10.1074/jbc.M700841200. PMIDÂ 17488724.
- Mollnes TE, Jokiranta TS, Truedsson L, Nilsson B, Rodriguez de Cordoba S, Kirschfink M (September 2007). "Complement analysis in the 21st century". Molecular Immunology. 44 (16): 3838â€“49. doi:10.1016/j.molimm.2007.06.150. hdl:10261/61732. PMIDÂ 17768101.
- Triggianese P, Chimenti MS, Toubi E, Ballanti E, Guarino MD, Perricone C, Perricone R (August 2015). "The autoimmune side of hereditary angioedema: insights on the pathogenesis". Autoimmunity Reviews. 14 (8): 665â€“9. doi:10.1016/j.autrev.2015.03.006. PMIDÂ 25827463.
- Nagai N, Hosokawa M, Itohara S, Adachi E, Matsushita T, Hosokawa N, Nagata K (September 2000). "Embryonic lethality of molecular chaperone hsp47 knockout mice is associated with defects in collagen biosynthesis". The Journal of Cell Biology. 150 (6): 1499â€“506. doi:10.1083/jcb.150.6.1499. PMCÂ 2150697. PMIDÂ 10995453.
- Marini JC, Reich A, Smith SM (August 2014). "Osteogenesis imperfecta due to mutations in non-collagenous genes: lessons in the biology of bone formation". Current Opinion in Pediatrics. 26 (4): 500â€“7. doi:10.1097/MOP.0000000000000117. PMCÂ 4183132. PMIDÂ 25007323.
- Byers PH, Pyott SM (1 January 2012). "Recessively inherited forms of osteogenesis imperfecta". Annual Review of Genetics. 46: 475â€“97. doi:10.1146/annurev-genet-110711-155608. PMIDÂ 23145505.
- Osterwalder T, Cinelli P, Baici A, Pennella A, Krueger SR, Schrimpf SP, Meins M, Sonderegger P (January 1998). "The axonally secreted serine proteinase inhibitor, neuroserpin, inhibits plasminogen activators and plasmin but not thrombin". The Journal of Biological Chemistry. 273 (4): 2312â€“21. doi:10.1074/jbc.273.4.2312. PMIDÂ 9442076.
- Crowther DC (July 2002). "Familial conformational diseases and dementias". Human Mutation. 20 (1): 1â€“14. doi:10.1002/humu.10100. PMIDÂ 12112652. S2CIDÂ 22326349.
- Belorgey D, HÃ¤gglÃ¶f P, Karlsson-Li S, Lomas DA (1 March 2007). "Protein misfolding and the serpinopathies". Prion. 1 (1): 15â€“20. doi:10.4161/pri.1.1.3974. PMCÂ 2633702. PMIDÂ 19164889.
- Ozaki K, Nagata M, Suzuki M, Fujiwara T, Miyoshi Y, Ishikawa O, Ohigashi H, Imaoka S, Takahashi E, Nakamura Y (July 1998). "Isolation and characterization of a novel human pancreas-specific gene, pancpin, that is down-regulated in pancreatic cancer cells". Genes, Chromosomes & Cancer. 22 (3): 179â€“85. doi:10.1002/(SICI)1098-2264(199807)22:3<179::AID-GCC3>3.0.CO;2-T. PMIDÂ 9624529.
- Loftus SK, Cannons JL, Incao A, Pak E, Chen A, Zerfas PM, Bryant MA, Biesecker LG, Schwartzberg PL, Pavan WJ (September 2005). "Acinar cell apoptosis in Serpini2-deficient mice models pancreatic insufficiency". PLOS Genetics. 1 (3): e38. doi:10.1371/journal.pgen.0010038. PMCÂ 1231717. PMIDÂ 16184191.
- Padua MB, Kowalski AA, CaÃ±as MY, Hansen PJ (February 2010). "The molecular phylogeny of uterine serpins and its relationship to evolution of placentation". FASEB Journal. 24 (2): 526â€“37. doi:10.1096/fj.09-138453. PMIDÂ 19825977. S2CIDÂ 9248169.
- Padua MB, Hansen PJ (October 2010). "Evolution and function of the uterine serpins (SERPINA14)". American Journal of Reproductive Immunology. 64 (4): 265â€“74. doi:10.1111/j.1600-0897.2010.00901.x. PMIDÂ 20678169.
- Reichhart JM (December 2005). "Tip of another iceberg: Drosophila serpins". Trends in Cell Biology. 15 (12): 659â€“65. doi:10.1016/j.tcb.2005.10.001. PMIDÂ 16260136.
- Tang H, Kambris Z, Lemaitre B, Hashimoto C (October 2008). "A serpin that regulates immune melanization in the respiratory system of Drosophila". Developmental Cell. 15 (4): 617â€“26. doi:10.1016/j.devcel.2008.08.017. PMCÂ 2671232. PMIDÂ 18854145.
- Scherfer C, Tang H, Kambris Z, Lhocine N, Hashimoto C, Lemaitre B (November 2008). "Drosophila Serpin-28D regulates hemolymph phenoloxidase activity and adult pigmentation". Developmental Biology. 323 (2): 189â€“96. doi:10.1016/j.ydbio.2008.08.030. PMIDÂ 18801354.
- Rushlow C (January 2004). "Dorsoventral patterning: a serpin pinned down at last". Current Biology. 14 (1): R16â€“8. doi:10.1016/j.cub.2003.12.015. PMIDÂ 14711428.
- Ligoxygakis P, Roth S, Reichhart JM (December 2003). "A serpin regulates dorsal-ventral axis formation in the Drosophila embryo". Current Biology. 13 (23): 2097â€“102. doi:10.1016/j.cub.2003.10.062. PMIDÂ 14654000.
- Jiang R, Zhang B, Kurokawa K, So YI, Kim EH, Hwang HO, Lee JH, Shiratsuchi A, Zhang J, Nakanishi Y, Lee HS, Lee BL (October 2011). "93-kDa twin-domain serine protease inhibitor (Serpin) has a regulatory function on the beetle Toll proteolytic signaling cascade". The Journal of Biological Chemistry. 286 (40): 35087â€“95. doi:10.1074/jbc.M111.277343. PMCÂ 3186399. PMIDÂ 21862574.
- Pak SC, Kumar V, Tsu C, Luke CJ, Askew YS, Askew DJ, Mills DR, BrÃ¶mme D, Silverman GA (April 2004). "SRP-2 is a cross-class inhibitor that participates in postembryonic development of the nematode Caenorhabditis elegans: initial characterization of the clade L serpins". The Journal of Biological Chemistry. 279 (15): 15448â€“59. doi:10.1074/jbc.M400261200. PMIDÂ 14739286.
- Luke CJ, Pak SC, Askew YS, Naviglia TL, Askew DJ, Nobar SM, Vetica AC, Long OS, Watkins SC, Stolz DB, Barstead RJ, Moulder GL, BrÃ¶mme D, Silverman GA (September 2007). "An intracellular serpin regulates necrosis by inhibiting the induction and sequelae of lysosomal injury". Cell. 130 (6): 1108â€“19. doi:10.1016/j.cell.2007.07.013. PMCÂ 2128786. PMIDÂ 17889653.
- Hejgaard J, Rasmussen SK, Brandt A, SvendsenI (1985). "Sequence homology between barley endosperm protein Z and protease inhibitors of the alpha-1-antitrypsin family". FEBS Lett. 180 (1): 89â€“94. doi:10.1016/0014-5793(85)80238-6. S2CIDÂ 84790014.
- Dahl SW, Rasmussen SK, Petersen LC, Hejgaard J (September 1996). "Inhibition of coagulation factors by recombinant barley serpin BSZx". FEBS Letters. 394 (2): 165â€“8. doi:10.1016/0014-5793(96)00940-4. PMIDÂ 8843156.
- Hejgaard J (January 2001). "Inhibitory serpins from rye grain with glutamine as P1 and P2 residues in the reactive center". FEBS Letters. 488 (3): 149â€“53. doi:10.1016/S0014-5793(00)02425-X. PMIDÂ 11163762. S2CIDÂ 27933086.
- Ostergaard H, Rasmussen SK, Roberts TH, Hejgaard J (October 2000). "Inhibitory serpins from wheat grain with reactive centers resembling glutamine-rich repeats of prolamin storage proteins. Cloning and characterization of five major molecular forms". The Journal of Biological Chemistry. 275 (43): 33272â€“9. doi:10.1074/jbc.M004633200. PMIDÂ 10874043.
- Yoo BC, Aoki K, Xiang Y, Campbell LR, Hull RJ, Xoconostle-CÃ¡zares B, Monzer J, Lee JY, Ullman DE, Lucas WJ (November 2000). "Characterization of cucurbita maxima phloem serpin-1 (CmPS-1). A developmentally regulated elastase inhibitor". The Journal of Biological Chemistry. 275 (45): 35122â€“8. doi:10.1074/jbc.M006060200. PMIDÂ 10960478.
- la Cour Petersen M, Hejgaard J, Thompson GA, Schulz A (December 2005). "Cucurbit phloem serpins are graft-transmissible and appear to be resistant to turnover in the sieve element-companion cell complex". Journal of Experimental Botany. 56 (422): 3111â€“20. doi:10.1093/jxb/eri308. PMIDÂ 16246856.
- Roberts TH, Hejgaard J (February 2008). "Serpins in plants and green algae". Functional & Integrative Genomics. 8 (1): 1â€“27. doi:10.1007/s10142-007-0059-2. PMIDÂ 18060440. S2CIDÂ 22960858.
- Lampl N, Alkan N, Davydov O, Fluhr R (May 2013). "Set-point control of RD21 protease activity by AtSerpin1 controls cell death in Arabidopsis". The Plant Journal. 74 (3): 498â€“510. doi:10.1111/tpj.12141. PMIDÂ 23398119.
- Ahn JW, Atwell BJ, Roberts TH (2009). "Serpin genes AtSRP2 and AtSRP3 are required for normal growth sensitivity to a DNA alkylating agent in Arabidopsis". BMC Plant Biology. 9: 52. doi:10.1186/1471-2229-9-52. PMCÂ 2689219. PMIDÂ 19426562.
- Kang S, Barak Y, Lamed R, Bayer EA, Morrison M (June 2006). "The functional repertoire of prokaryote cellulosomes includes the serpin superfamily of serine proteinase inhibitors". Molecular Microbiology. 60 (6): 1344â€“54. doi:10.1111/j.1365-2958.2006.05182.x. PMIDÂ 16796673. S2CIDÂ 23738804.
- Irving JA, Cabrita LD, Rossjohn J, Pike RN, Bottomley SP, Whisstock JC (April 2003). "The 1.5 A crystal structure of a prokaryote serpin: controlling conformational change in a heated environment". Structure. 11 (4): 387â€“97. doi:10.1016/S0969-2126(03)00057-1. PMIDÂ 12679017.
- Fulton KF, Buckle AM, Cabrita LD, Irving JA, Butcher RE, Smith I, Reeve S, Lesk AM, Bottomley SP, Rossjohn J, Whisstock JC (March 2005). "The high resolution crystal structure of a native thermostable serpin reveals the complex mechanism underpinning the stressed to relaxed transition". The Journal of Biological Chemistry. 280 (9): 8435â€“42. doi:10.1074/jbc.M410206200. PMIDÂ 15590653.
- Turner PC, Moyer RW (September 2002). "Poxvirus immune modulators: functional insights from animal models". Virus Research. 88 (1â€“2): 35â€“53. doi:10.1016/S0168-1702(02)00119-3. PMIDÂ 12297326.
- Richardson J, Viswanathan K, Lucas A (2006). "Serpins, the vasculature, and viral therapeutics". Frontiers in Bioscience. 11: 1042â€“56. doi:10.2741/1862. PMIDÂ 16146796.
- Jiang J, Arp J, Kubelik D, Zassoko R, Liu W, Wise Y, Macaulay C, Garcia B, McFadden G, Lucas AR, Wang H (November 2007). "Induction of indefinite cardiac allograft survival correlates with toll-like receptor 2 and 4 downregulation after serine protease inhibitor-1 (Serp-1) treatment". Transplantation. 84 (9): 1158â€“67. doi:10.1097/01.tp.0000286099.50532.b0. PMIDÂ 17998872. S2CIDÂ 20168458.
- Dai E, Guan H, Liu L, Little S, McFadden G, Vaziri S, Cao H, Ivanova IA, Bocksch L, Lucas A (May 2003). "Serp-1, a viral anti-inflammatory serpin, regulates cellular serine proteinase and serpin responses to vascular injury". The Journal of Biological Chemistry. 278 (20): 18563â€“72. doi:10.1074/jbc.M209683200. PMIDÂ 12637546.
- Turner PC, Sancho MC, Thoennes SR, Caputo A, Bleackley RC, Moyer RW (August 1999). "Myxoma virus Serp2 is a weak inhibitor of granzyme B and interleukin-1beta-converting enzyme in vitro and unlike CrmA cannot block apoptosis in cowpox virus-infected cells". Journal of Virology. 73 (8): 6394â€“404. doi:10.1128/JVI.73.8.6394-6404.1999. PMCÂ 112719. PMIDÂ 10400732.
- Munuswamy-Ramanujam G, Khan KA, Lucas AR (December 2006). "Viral anti-inflammatory reagents: the potential for treatment of arthritic and vasculitic disorders". Endocrine, Metabolic & Immune Disorders Drug Targets. 6 (4): 331â€“43. doi:10.2174/187153006779025720. PMIDÂ 17214579.
- Renatus M, Zhou Q, Stennicke HR, Snipas SJ, Turk D, Bankston LA, Liddington RC, Salvesen GS (July 2000). "Crystal structure of the apoptotic suppressor CrmA in its cleaved form". Structure. 8 (7): 789â€“97. doi:10.1016/S0969-2126(00)00165-9. PMIDÂ 10903953.
- PDB Molecule of the Month Serpin
- Merops protease inhibitor claudication (Family I4)
- Serpins at the US National Library of Medicine Medical Subject Headings (MeSH)
- James Whisstock laboratory at Monash University
- Jim Huntington laboratory Archived 30 October 2016 at the Wayback Machine at University of Cambridge
- Frank Church laboratory at University of North Carolina at Chapel Hill
- Paul Declerck laboratory at Katholieke Universiteit Leuven
- Tom Roberts laboratory at University of Sydney
- Robert Fluhr laboratory at Weizmann Institute of Science
- Peter Gettins laboratory at University of Illinois at Chicago
- Overview of all the structural information available in the PDB for UniProt: P01009 (Human Alpha-1-antitrypsin) at the PDBe-KB.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Serpin (serine protease inhibitor) Provide feedback
Structure is a multi-domain fold containing a bundle of helices and a beta sandwich.
Internal database links
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR023796
Serpins (SERine Proteinase INhibitors) belong to MEROPS inhibitor family I4, clan ID. Most serpin family members are indeed serine protease inhibitors, but several have additional cross-class inhibition functions and inhibit cysteine protease family members such as the caspases and cathepsins [ PUBMED:8034697 , PUBMED:7851535 ]. Others, such as ovalbumin, are incapable of protease inhibition and serve other functions [ PUBMED:8417965 ].
Serpins share a highly conserved core structure that is critical for their functioning as serine protease inhibitors [ PUBMED:21781239 ]. Inhibitory serpins comprise several alpha-helix and beta-strands together with an external reactive centre loop (RCL) containing the active site recognised by the target enzyme. Serpins form covalent complexes with target proteases. Their mechanism of protease inhibition is known as irreversible "trapping" , in which a rapid conformational change traps the cognate protease in a covalent complex.
This entry represents the structural domain of serpins.
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
Loading domain graphics...
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Seed source:||Overington and HMM_iterative_training|
|Number in seed:||113|
|Number in full:||20221|
|Average length of the domain:||302.30 aa|
|Average identity of full alignment:||24 %|
|Average coverage of the sequence by the domain:||83.75 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||23|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Serpin domain has been found. There are 498 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
Loading structure mapping...
AlphaFold Structure Predictions
The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.