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369  structures 463  species 7  interactions 4827  sequences 42  architectures

Family: Serpin (PF00079)

Summary: Serpin (serine protease inhibitor)

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Serpin (serine protease inhibitor)
Figure 1: Recent serpin structures: the structure of the serpin protein Z-dependent inhibitor (PZI - in green/magenta) in complex with protein Z (cyan/red). Protein Z itself is a catalytically inactive serine protease that functions in this instance as a co-factor. The PZI / Protein Z complex is a highly effective inhibitor of the coagulation protease factor Xa.[1]
Symbol Serpin
Pfam PF00079
InterPro IPR000215
SCOP 1hle
CDD cd00172

Serpins are a group of proteins with similar structures that were first identified as a set of proteins able to inhibit proteases. The acronym serpin was originally coined because many serpins inhibit chymotrypsin-like serine proteases (serine protease inhibitors).[2][3][4]

The first members of the serpin superfamily to be extensively studied were the human plasma proteins antithrombin and antitrypsin, which play key roles in controlling blood coagulation (e.g. Figure 1) and inflammation, respectively. Initially, research focused upon their role in human disease: antithrombin deficiency results in thrombosis and antitrypsin deficiency causes emphysema. In 1980 Hunt and Dayhoff made the surprising discovery that both these molecules share significant amino acid sequence similarity to the major protein in chicken egg white, ovalbumin, and they proposed a new protein superfamily.[5] Over 1000 serpins have now been identified, these include 36 human proteins, as well as molecules in plants, fungi, bacteria, archaea and certain viruses.[6][7][8] Serpins are thus the largest and most diverse family of protease inhibitors.[9]

While most serpins control proteolytic cascades, certain serpins do not inhibit enzymes, but instead perform diverse functions such as storage (ovalbumin, in egg white), hormone carriage proteins (thyroxine-binding globulin, cortisol-binding globulin) and molecular chaperones (HSP47). The term serpin is used to describe these latter members as well, despite their noninhibitory function.[10]

As serpins control processes such as coagulation and inflammation, these proteins are the target of medical research. However, serpins are also of particular interest to the structural biology and protein folding communities, because they undergo a unique and dramatic change in shape (or conformational change) when they inhibit target proteases.[11] This is unusual — most classical protease inhibitors function as simple "lock and key" molecules that bind to and block access to the protease active site (see, for example, bovine pancreatic trypsin inhibitor). While the serpin mechanism of protease inhibition confers certain advantages, it also has drawbacks, and serpins are vulnerable to mutations that result in protein misfolding and the formation of inactive long-chain polymers (serpinopathies).[12][13][14] Serpin polymerisation reduces the amount of active inhibitor, as well as accumulation of serpin polymers, causing cell death and organ failure. For example, the serpin antitrypsin is primarily produced in the liver, and antitrypsin polymerisation causes liver cirrhosis.[14] Understanding serpinopathies also provides insights on protein misfolding in general, a process common to many human diseases, such as Alzheimer's and Creutzfeldt-Jakob disease.[13]

Cross-class inhibitors

Figure 2: The X-ray crystal structure of the archetypal serine protease chymotrypsin (pdb code 4CHA).[15] The three catalytic residues (His 57, Asp 102 and Ser 195) are labeled.

Most inhibitory serpins target chymotrypsin-like serine proteases (see Table 1 and Figure 2). These enzymes are defined by the presence of a nucleophilic serine residue in their catalytic site. Examples include thrombin, trypsin, and human neutrophil elastase.[16]

Some serpins inhibit other classes of protease and are termed "cross-class inhibitors". A number of such serpins have been shown to target cysteine proteases. These enzymes differ from serine proteases in that they are defined by the presence of a nucleophilic cysteine residue, rather than a serine residue, in their catalytic site.[17] Nonetheless, the enzymatic chemistry is similar, and serpins most likely inhibit both classes of enzyme in a similar fashion.[18]

Examples of cross-class inhibitory serpins include squamous cell carcinoma antigen 1 (SCCA-1) and the avian serpin myeloid and erythroid nuclear termination stage-specific protein (MENT) both inhibit papain-like cysteine proteases[19][20][21]

The viral serpin crmA is a suppressor of the inflammatory response through inhibition of IL-1 and IL-18 processing by the cysteine protease caspase-1.[22] In eukaryotes, a plant serpin has been shown to inhibit metacaspases[23] and a papain-like cysteine protease.[24] It is presently unclear whether any mammalian serpins function to inhibit caspases in vivo.

Localization and roles

Figure 3: The hormone cortisol bound to the serpin corticosteroid-binding globulin.[25]

Approximately two-thirds of human serpins perform extracellular roles. For example, extracellular serpins regulate the proteolytic cascades central to blood clotting (antithrombin), the inflammatory response (antitrypsin, antichymotrypsin, and C1 inhibitor) and tissue remodeling (PAI-1). Non-inhibitory extracellular serpins also perform important roles. Thyroxine-binding globulin and cortisol-binding globulin transport the sterol hormones thyroxine and cortisol, respectively (Figure 3).[25][26] The protease renin cleaves off a ten-amino acid N-terminal peptide from angiotensinogen to produce the peptide hormone angiotensin I.[27] Table 1 provides a brief summary of human serpin function, as well as some of the diseases that result from serpin deficiency.

The first Intracellular members of the serpin superfamily were identified in the early 1990s.[28][29] As all nine serpins in Caenorhabditis elegans lack signal sequences, they are probably intracellular.[30] Based upon these data it seems likely that the ancestral serpin to human serpins was an intracellular molecule.

The protease targets of intracellular inhibitory serpins have been more difficult to identify. Characterization is complicated by the observation that many of these molecules appear to perform overlapping roles. Further many human serpins lack precise functional equivalents in model organisms such as the mouse. An important function of intracellular serpins may be to protect against the inappropriate activity of proteases inside the cell.[31] For example, one of the best-characterised human intracellular serpins is SERPINB9, which inhibits the cytotoxic granule protease granzyme B. In doing so, SERPINB9 may protect against inadvertent release of granzyme B and premature or unwanted activation of cell death pathways.[32]

Intracellular serpins also perform roles distinct from protease inhibition. For example, the avian nuclear cysteine protease inhibitor MENT, acts as a chromatin remodelling molecule in avian red blood cells.[20][33]

Phylogenetic studies show that most intracellular serpins belong to a single clade (see Table 1). Exceptions include the non-inhibitory heat shock serpin HSP47, which is a chaperone essential for proper folding of collagen, and cycles between the cis-Golgi and the endoplasmic reticulum.[34]


Figure 4a: The X-ray crystal structure of native human antitrypsin (pdb code 1QLP).[35] The five-stranded A-sheet is in red, the six-stranded B-sheet in green, and the four-stranded C-sheet in yellow. α-helices are shown in cyan. The RCL is at the top of the molecule in magenta. Two functionally important regions of the serpin, the breach and the shutter, are labelled. The figure was produced using PYMOL Figure 4b: The structure of native murine antichymotrypsin (pdb code 1YXA).[36] Colouring is as for figure 4a. Note that two amino acids of the RCL are partially inserted into the top of the A β-sheet (in red).

Structural biology has played a central role in the understanding of serpin function and biology. Over eighty serpin structures, in a variety of different conformations (described below), have been determined to date. Although the function of serpins varies widely, these molecules all share a common structure (or fold).

The structure of the non-inhibitory serpin ovalbumin, and the inhibitory serpin antitrypsin, revealed the archetype native serpin fold.[37][38] All typically have three β-sheets (termed A, B and C) and eight or nine α-helices (hA-hI) (see figure 4). Serpins also possess an exposed region termed the reactive centre loop (RCL) that, in inhibitory molecules, includes the specificity determining region and forms the initial interaction with the target protease. In antitrypsin, the RCL is held at the top of the molecule and is not pre-inserted into the A β-sheet (figure 4, left panel). This conformation commonly exists in dynamic equilibrium with a partially inserted native conformation[39] seen in other inhibitory serpins (see figure 4, right panel).

Conformational change and inhibitory mechanism

Early studies on serpins revealed that the mechanism by which these molecules inhibit target proteases appeared distinct from the lock-and-key-type mechanism utilised by small protease inhibitors such as the Kunitz-type inhibitors (e.g. basic pancreatic trypsin inhibitor). Indeed, serpins form covalent complexes with target proteases.[40] Structural studies on serpins also revealed that inhibitory members of the family undergo an unusual conformational change, termed the Stressed to Relaxed (S to R) transition.[37][39][41][42] During this structural transition the RCL inserts into β-sheet A (in red in figure 4 and 5) and forms an extra (fourth) β-strand. The serpin conformational change is key to the mechanism of inhibition of target proteases.

When attacking a substrate, serine proteases catalyze peptide bond cleavage in a two-step process. Initially, the catalytic serine performs a nucleophilic attack on the peptide bond of the substrate (Figure 5). This releases the new N-terminus and forms an ester-bond between the enzyme and the substrate. This covalent enzyme-substrate complex is called an acyl enzyme intermediate. Subsequent to this, this ester bond is hydrolysed and the new C-terminus is released. The RCL of a serpin acts as a substrate for its cognate protease. However, after the RCL is cleaved, but prior to hydrolysis of the acyl-enzyme intermediate, the serpin rapidly undergoes the S-to-R transition. Since the RCL is still covalently attached to the protease via the ester bond, the S-to-R transition causes the protease to be moved from the top to the bottom of the serpin. At the same time, the protease is distorted into a conformation, where the acyl enzyme intermediate is hydrolysed extremely slowly.[11] The protease thus remains covalently attached to the target protease and is thereby inhibited. Further, since the serpin has to be cleaved to inhibit the target protases, inhibition consumes the serpin as well. Serpins are therefore irreversible enzyme inhibitors. The serpin mechanism of inhibition is illustrated in figures 5 and 6, and several movies illustrating the serpin mechanism can be viewed at this link.

Mechanism of protease inhibition by serpins
Figure 5:
Left: Structure of the non-covalent complex between insect Serpin1K and inactive rat trypsin (pdb code 1K9O).[43] To trap the encounter complex the trypsin (orange) was mutated to an inactive form unable to cleave the RCL. Serpin colouring is as for figure 4.
Right: Final complex between antitrypsin and active trypsin (pdb code 1EZX).[11] The figure was produced using PYMOL.
Figure 6: Catalytic mechanism of serine proteases (adapted from Serine protease mechanism) illustrating the stage in the cycle that is trapped by serpin inhibitors (magenta circle). The ester bond in the acyl enzyme intermediate is highlighted in red.

Conformational modulation of serpin activity

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 readily controlled by 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 β-sheet (see figures 4 and 7). The partially inserted conformation is important because co-factors are able to conformationally switch certain partially inserted serpins into a fully expelled form.[44][45] 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 (Figure 7). Upon binding a high-affinity heparin 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 (figure 7).[46][47] Furthermore, both of these coagulation proteases 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 (Figure 7). 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. The understanding of the molecular basis of this interaction formed the basis of the development of Fondaparinux, a synthetic form of Heparin pentasaccharide used as an anti-clotting drug.[48]

Figure 7:
From left to right.
1. The partially inserted conformation of native antithrombin. The P1 Arginine is in purple spheres (from pdb 2ANT).
2. Binding of the high affinity heparin pentasaccharide sequence (in cyan spheres) within long chain heparin (in yellow spheres) (from pdb 1TB6).
Note how the P1 Arginine residue has flipped to a more exposed position.
3. Initial interaction of thrombin (orange) with the RCL. Thrombin also contains a binding site for heparin (from pdb 1TB6).
4. Following docking, the final serpin enzyme complex is formed (illustrated using the antitrypsin / trypsin complex) and heparin is released (from pdb 1EZX).

Certain serpins spontaneously undergo the S-to-R transition as part of their function, to form a conformation termed the latent state (Figure 8). In latent serpins, the first strand of the C-sheet has to peel off to allow full RCL insertion. Latent serpins are unable to interact with proteases and are not protease inhibitors. The transition to latency represents a control mechanism for the serpin PAI-1. PAI-1 is released in the inhibitory conformation, however, undergoes conformational change to the latent state unless it is bound to the cofactor vitronectin.[49] Thus PAI-1 contains an "auto-inactivation" mechanism. Similarly, antithrombin can also spontaneously convert to the latent state as part of its normal function. Finally, the N-terminus of tengpin (see pdbs 2PEE and 2PEF), 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.[50][51]

Figure 8a: X-ray crystal structure of native PAI-1 (from pdb 1DVM) (stabilised though mutation). The RCL is in magenta, and the first β-strand of the C-β-sheet in yellow. In the absence of vitronectin, PAI-1 converts to the latent form (right) (from pdb 1LJ5). The first strand of the C-sheet has peeled off to allow full RCL insertion.
Figure 8b: Structure of native PAI-1 bound to vitronectin (in cyan) (from pdb 1OCO). Part of the RCL is disordered in this structure and is represented by a dashed line.

Serpin receptor interactions

In humans, extracellular serpin-enzyme complexes are rapidly cleared from circulation. In mammals, one mechanism by which this occurs is via the low-density lipoprotein receptor-related protein (LRP receptor), which binds to inhibitory complexes made by antithrombin, PA1-1, and neuroserpin, causing uptake and subsequent signaling events.[52][53] Thus, as a consequence of the conformational change during serpin-enzyme complex formation, serpins may act as signaling molecules that alert cells to the presence of protease activity.[52] The fate of intracellular serpin-enzyme complexes remains to be characterised.

Recently, it has been shown that the Drosophila serpin necrotic is taken up via the Lipophorin Receptor-1 (LpR1), which is related to the mammalian LDL receptor family. Trafficking studies reveal that following uptake by LpR1, necrotic is delivered to lysosomes where it is targeted for degradation.[54]

Conformational change and non-inhibitory function

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. In similar manner, native (S) Cortisol-Binding Globulin (CBG) has higher affinity for cortisol than its cleaved (R) counterpart (Figure 3). Thus, in these serpins, RCL cleavage and the S to R transition has been commandeered to allow for ligand release, rather than protease inhibition.[25][26][55]

Serpins, serpinopathies and human disease

Figure 9: Model illustrating the ideas behind the proposed A-sheet mechanism of serpin polymerisation.[14][56] The A β-sheet is in red. The RCL (magenta) of the orange molecule is inserted into the bottom of the A-sheet of the white molecule.

Serpins are vulnerable to inactivating disease-causing mutations that result in the formation of misfolded polymers or protein aggregates ("serpinopathies"). Well-characterised serpinopathies include alpha 1-antitrypsin deficiency (alpha-1), which may cause familial emphysema and sometimes liver cirrhosis, certain familial forms of thrombosis related to antithrombin deficiency, types 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).[13][14] Serpins thus belong to a large group of molecules such as the prion proteins and the glutamine repeat containing proteins that cause proteopathies or conformational diseases.[13]

Serpin polymerisation causes disease in two ways. First, the lack of active serpin results in uncontrolled protease activity and tissue destruction; this is seen in the case of antitrypsin deficiency. Second, the 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 removed via endoplasmic reticulum associated degradation.[57] However, the mechanism by which serpin polymers cause cell death remains to be fully understood.

Like cleaved serpins, serpin polymers are hyperstable with respect to heating, and each serpin monomer appears to have undergone the stressed to relaxed transition. Furthermore, serpin polymers are unable to inhibit target proteases, suggesting that the RCL is unavailable and inserted into the A-sheet. In the absence of definitive structural data, it was, therefore, postulated that serpins polymerise via a mechanism known as A-sheet polymerisation.[14] In normal function the RCL inserts into the A β-sheet to form a fourth strand (figure 4). In the A-sheet polymerisation model, it was suggested that the RCL of one serpin molecule spontaneously inserted into the A-sheet of another, to form a long-chain polymer (figure 9). In effect, it was, thus, proposed that polymerization occurred as a consequence of the requirement of the serpin scaffold to accept an additional β-strand.

Serpins were one of the first families for which disease-causing mutations were directly analyzed in reference to the available crystal structures.[58] In support of the A-sheet polymerisation model, it was noted that many serpin mutations that cause polymerisation localise to two distinct regions of the molecule (highlighted in figure 4a) termed the shutter and the breach. The shutter and the breach contain highly conserved residues, underlie the path of RCL insertion, and are proposed to be important for conformational change.

Two structures of cleaved serpin polymers have been solved; both of which reveal RCL / A-sheet sheet linkages similar to those predicted by the A sheet polymerisation mechanism.[59][60] However, in direct contrast to the known properties of physiological serpin polymers, crystals of cleaved serpin A-sheet polymers readily dissociate into monomeric forms.[59][60]

Figure 10: The structure of a domain swapped antithrombin dimer reveals one mechanism via which serpins can polymerise (pdb code 2ZNH).[12]

A large body of data now suggest that the events associated with serpin polymerisation occur during the folding of the molecule, and that mutations that cause serpinopathies interfere with the ability of the serpin to fold to the metastable native state.[61] In normal serpin folding, the serpin rapidly moves through a key folding intermediate to attain the native state. Many studies have shown that it is the serpin folding intermediate that has the ability to polymerise, hence it is important that this folding species rapidly moves on to adopt native state. It was shown that mutations such as the Z-antitrypsin variant (Glu 342 to Lys) somehow prevented the final stage of seprin folding and caused the accumulation of the folding intermediate. As a result, population of the folding intermediate resulted in polymer formation.[61] It was noted that once folded, the Z-antitrypsin variant closely resembles wild-type material in terms of thermal stability and inhibitory activity.[61][62]

Together, these data have presented an important challenge to the A-sheet model for serpin polymerisation. On the one hand, the idea that serpin polymer formation essentially takes advantage of the serpin mechanism of conformational change is an attractive one. On the other, the biophyiscal data in particular suggest that it is a folding intermediate (rather than the native form) that polymerises, and it is clear that this intermediate must have different structural properties to the native, folded state.

In 2008, a key serpin crystal structure was determined that strongly suggests that physiological serpin polymers do not form via the A-sheet mechanism and instead form via a more extensive domain swapping event.[12] The first such structure solved was of an antithrombin dimer (figure 10), and revealed that both strands s5A and the RCL can be incorporated into the A-sheet of another serpin molecule. This structure can readily be adapted to form long chain polymers.[12] In 2011, the structure of a domain swapped antitrypsin trimer revealed that in polymers of this serpin the RCL is inserted, and that the C-terminal region of the molecule (comprising strands s1C, s4B and s5B) formed the domain swap (figure 11).[63] In support of the physiological relevance of the latter structure, it was shown that antitrypsin polymers formed via a C-terminal domain swap were recognised by a monocloncal antibody[64] specific for pathogenic antitrypsin polymers.[63]

Figure 11: The structure of an antitrypsin trimer formed via domain swapping of the C-terminal region.[63] In the green molecule the inserted RCL is shown in red (pdb code 3T1P). The region that is domain swapped into the neighbouring molecule comprises s1C, s4B and s5B.

The new "domain swapped" model for serpin polymerisation begins to reconcile the available biophysical and biochemical data. Together, these data suggest that domain swapping events occur when mutations or environmental factors somehow interfere with the final stages of serpin folding to the native state. These data also reveal that different serpins can apparently polymerise via different types of domain swaps. Finally, while these data shed light on the final polymeric form, it is important to note that the precise toxic species of intermediate and / or polymer that causes cell death in, for example, antitrypsin deficiency, remains to be identified.[65]

Development of therapeutic strategies to combat serpinopathies

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 pulmonary emphysema.[66] Lung and / or liver transplantation is also used to treat severe antitrypsin deficiency-related disease.[67] In animal models, gene targeting in induced pluripotent stem cells has successfully been deployed to correct the Z-antitrypsin defect and to restore the ability of the mammalian liver to secrete active antitrypsin.[68] A number of groups have also reported small molecules that block antitrypsin polymerisation in vitro.[69][70]

Mutations that result in spontaneous formation of latent (or latent-like), inactive conformations

Figure 12: X-ray crystal structure of the δ-conformation of the Leucine 55 to Proline mutation of antichymotrypsin (from pdb 1QMN). Four residues of the RCL (magenta; dashed line indicates disordered region) are inserted into the top of the A β-sheet. Part of the F α-helix (cyan) has unwound and fills the bottom half of the A β-sheet.[71]

Certain pathogenic mutations in serpins can promote inappropriate transition to the monomeric latent state (see figure 8a for the structure of the latent state). This causes disease because it reduces the amount of active inhibitory serpin. For example, the disease-linked antithrombin variants wibble and wobble,[72] both promote formation of the latent state.

It is also worth highlighting a structure of a disease-linked human antichymotrypsin variant that further demonstrates the extraordinary flexibility of the serpin scaffold. The structure of antichymotrypsin (Leucine 55 to Proline) revealed a novel "δ" conformation that may represent an intermediate between the native and latent state (Figure 12). In the delta conformation, four residues of the RCL are inserted into the top of β-sheet A. The bottom half of the sheet is filled as a result of one of the α-helices (the F-helix) partially switching to a β-strand conformation, completing the β-sheet hydrogen bonding.[71] It is unclear whether other serpins can adopt this conformer, and whether this conformation has a functional role. However, it is speculated that the δ-conformation may be adopted by Thyroxine-binding globulin during thyroxine release.[26]

Other mechanisms of serpin-related disease

In humans, simple deficiency of many serpins (e.g., through a null mutation) may result in disease (see Table 1).

It is rare that single amino acid changes in the RCL of a serpin alters the specificity of the inhibitor and allow it to target the wrong protease. For example, the Antitrypsin-Pittsburgh mutation (methionine 358 to arginine) allowed the serpin to inhibit thrombin, thus causing a bleeding disorder.[73]

Serpins are suicide inhibitors, the RCL acting as a "bait." Certain disease-linked mutations in the RCL of human serpins permit true substrate-like behaviour and cleavage without complex formation. Such variants are speculated to affect the rate or the extent of RCL insertion into the A-sheet. These mutations, in effect, result in serpin deficiency through a failure to properly control the target protease.[58][74]

Several non-inhibitory serpins play key roles in important human diseases. For example, mutations in SERPINF1 cause osteogenesis imperfecta type VI in humans.[75]


Serpins were initially believed to be restricted to eukaryote organisms, but have since been found in a number of bacteria and archaea.[6][7][76] It remains unclear whether these prokaryote genes are the descendants of an ancestral prokaryotic serpin or the product of lateral gene transfer (genetic transfer between organisms not by evolutionary descent). Rawlings et al. showed that serpins are the most widely distributed and largest family of protease inhibitors.[9]

Types of serpins


In 2001, a serpin nomenclature was established (see table 1, below).[10] The naming system is based upon a phylogenetic analysis of ~500 serpins.[6] The human genome encodes 16 serpin clades, termed serpinA through to serpinP, encoding 29 inhibitory and 7 non-inhibitory serpin proteins (see Law et al. (2006) & Heit et al. (2013) for recent reviews).[77][78] The proteins are named serpinXY where X is the clade of the protein and Y the number of the protein within that clade. Table 1 lists each human serpin, together with brief notes in regards to each molecules function and the consequence (where known) of dysfunction or deficiency.

Table 1

Protein name PDB Common Name Description Disease / Effect of deficiency Chromosomal location
Alpha 1-antitrypsin extracellular, inhibits human neutrophil elastase.[79] Deficiency results in emphysema, antitrypsin polymerisation results in cirrhosis. Serpinopathy.[14] The C-terminal fragment of cleaved SERPINA1 may inhibit HIV-1 infection.[80] 14q32.1
SERPINA2 Antitrypsin-related protein extracellular, possible pseudogene[81] Unknown 14q32.1
Alpha 1-antichymotrypsin Extracellular, inhibits cathepsin G.[83] Reported to play a role in controlling chromatin condensation in hepatic cells.[84] Deficiency results in emphysema. Serpinopathy[71] 14q32.1
SERPINA4 Kallistatin extracellular, inhibition of kallikrein, regulation of vascular function[85][86] Depletion of Kallistatin in hypertensive rats enhanced renal and cardiovascular injury.[87] 14q32.1
Protein C inhibitor Extracellular, inhibitor of active protein C.[90] Intracellular role in preventing phagocytosis of bacteria.[91] Male murine knockouts are infertile[92] In multiple sclerosis, accumulation of PCI has been noted in chronic active plaques.[93] 14q32.1
Cortisol binding globulin Extracellular, non-inhibitory; cortisol binding.[25] Deficiency may cause chronic fatigue[94] 14q32.1
Thyroxine-binding globulin extracellular, non-inhibitory; thyroxine binding[26] Deficiency causes hypothyroidism.[95] Xq22.2
Angiotensinogen Extracellular; non-inhibitory, cleavage by renin results in release of angiotensin I.[97] Variants linked to hypertension[98] Murine knockouts result in hypotension.[99] 1q42-q43
SERPINA9 Centerin / GCET1 Extracellular; inhibitory, maintenance of naive B cells[100][101] Strongly expressed in most B-cell lymphomas.[102][103] 14q32.1
Protein Z-related protease inhibitor extracellular, binds protein Z and inactivates factor Xa and factor XIa[106] Deficiency may cause venous thromboembolic disease[107] 14q32.1
SERPINA11 - probably extracellular, not characterised. Unknown 14q32.13
SERPINA12 4IF8[108] Vaspin extracellular, insulin-sensitizing adipocytokine.[109] Inhibitor of Kallikrein-7 High plasma levels of SERPINA12 are correlated with insulin resistance in Type II Diabetes.[110] 14q32.1
SERPINA13 - probably extracellular, not characterised Unknown 14q32
SERPINB1 1HLE[111] Monocyte neutrophil elastase inhibitor Intracellular, inhibition of neutrophil elastase[112] Murine knockout results in neutrophil survival defect and immune deficiency[113] 6p25
SERPINB2 1BY7[114] Plasminogen activator inhibitor-2 Intracellular/extracellular. Inhibition of extracellular uPA. Intracellular function unclear, however, may protect against viral infection.[115] Murine knockouts viable / no obvious phenotype.[116] SERPINB2 deficient mice are less able to mount an immune response to nematode infection.[117] 18q21.3
SERPINB3 2ZV6[118] Squamous cell carcinoma antigen-1 (SCCA-1) Intracellular, inhibitor of papain-like cysteine proteases[19] Mice lacking Serpinb3a (the murine homolog of human SERPINB3 and SERPINB4) have reduced mucus production in a murine model of asthma.[119] 18q21.3
SERPINB4 Squamous cell carcinoma antigen-2 (SCCA-2) Intracellular, inhibitor of cathepsin G and chymase[120] Mice lacking Serpinb3a (the murine homolog of human SERPINB3 and SERPINB4) have reduced mucus production in a murine model of asthma.[119] 18q21.3
SERPINB5 1WZ9[121] Maspin Obligate intracellular serpin,[122] non inhibitory, originally proposed to function as a tumour suppressor.[123] Another study was unable to reproduce these findings and found no role for maspin in tumour biology.[124] Murine maspin knockouts originally reported to be lethal,[125] A subsequent study, however, reported that maspin knockout mice are viable and display no obvious phenotype.[124] From a disease perspective is suggested that maspin may be a prognostic indicator that reflects expression of a neighbouring known tumour suppressor gene (the phosphatase PHLPP1).[124] 18q21.3
SERPINB6 PI-6 intracellular, inhibition of cathepsin G[126] Murine knockout reveals mild neutropenia.[127] In humans, a nonsense mutation in SERPINB6 results in moderate to severe hearing loss.[128][129] 6p25
SERPINB7 Megsin intracellular, involved in megakaryocyte maturation[130] Studies on transgenic mice reveal megsin over-expression causes kidney disease.[131] Histological abnormalities are, however, not apparent in Megsin knockout mice.[131] Mutations in humans are associated with Nagashima-type Palmoplantar Keratosis[132][133] 18q21.3
SERPINB8 PI-8 intracellular; possible furin inhibitor[134] Genome wide association studies suggest that the SERPINB8 locus is linked with the development of Psoriasis.[135][136] 18q21.3
SERPINB9 PI-9 intracellular, inhibitor of the cytotoxic granule protease granzyme B[137] murine knockout reveals immune dysfunction[138][139] 6p25
SERPINB10 Bomapin intracellular, unknown function[140] Analysis of murine genomic material (C57/BL6; the common lab strain) reveals a stop codon in this gene (BC069938). In contrast, EST data suggests that full length bomapin is expressed in Czech II mice. These data suggest that loss of Bomapin function in mice does not result in an overt phenotype. 18q21.3
SERPINB11 intracellular, unknown function[141] Murine Serpinb11 is an active inhibitor whereas the human orthalogue is inactive.[141] Serpinb11 deficiency is associated with hoof wall separation disease in Connemara Ponies.[142] 18q21.3
SERPINB12 Yukopin intracellular, unknown function[143] Unknown 18q21.3
SERPINB13 Hurpin/Headpin intracellular, inhibitor of papain-like cysteine proteases[144] Unknown 18q21.3
Antithrombin Extracellular, inhibitor of coagulation, specifically factor X, factor IX and thrombin[145] Deficiency results in thrombosis and other clotting disorders. Serpinopathy[146] 1q23-q21
Heparin cofactor II extracellular, thrombin inhibitor[148] Murine knockouts are lethal.[149] 22q11
Plasminogen activator inhibitor 1 Extracellular; inhibitor of thrombin, uPA and TPa.[152] Cardiovascular disease, tumour progression[153][154] 7q21.3-q22
SERPINE2 4DY0[155] Glia derived nexin / Protease nexin I Extracellular, inhibition of uPA and tPA.[156] Abnormal expression leads to human male infertility.[157] Knockout mice also develop epileptic phenotype.[158] 2q33-q35
SERPINF1 1IMV[159] Pigment epithelium derived factor Extracellular, non-inhibitory, potent anti-angiogenic molecule.[160] PEDF has been reported to bind the glycosaminoglycan hyaluronan.[161] Murine knockout studies reveal that SERPINF1 regulates the vasculature and mass of the pancreas and the prostate.[160] Further, SERPINF1 has been demonstrated to promote Notch–dependent renewal of adult periventricular neural stem cells.[162] Human mutations in SERPINF1 cause osteogenesis imperfecta type VI.[75] 17p13.3
SERPINF2 2R9Y[163] Alpha 2-antiplasmin extracellular, plasmin inhibitor, inhibitor of fibrinolysis.[164] Bleeding disorder[165] 17pter-p12
SERPING1 2OAY[166] Complement 1-inhibitor Extracellular, C1 esterase inhibitor.[166] Angiodemia, serpinopathy.[167] Several polymorphisms in the SERPING1 gene are strongly associated with development of age-related macular degeneration and blindness.[168] 11q11-q13.1
SERPINH1 4AXY[169] 47 kDa Heat shock protein (HSP47) intracellular, non inhibitory, molecular chaperone in collagen folding.[170] Murine knockouts are lethal.[171] A missense mutation in human SERPINH1 results in severe osteogenesis imperfecta.[172][173] 11p15
Neuroserpin Extracellular, inhibitor of tPA, uPA and plasmin[176] Mutated in dementia (FENIB). Serpinopathy[177] 3q26
SERPINI2 Pancpin Extracellular, unknown protease target.[178] Studies on the Pequeño mouse line revealed that loss of SERPINI2 results in pancreatic insufficiency through pancreatic acinar cell loss.[179] In addition a possible role for SERPINI2 in inhibition of pancreatic cancer metastasis has been suggested.[178] 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 (discussed below).


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 uterine endometrium of a restricted group of mammals in the Laurasiatheria clade under the influence of progesterone or estrogen.[180] 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.[181]


The Drosophila melanogaster genome contains 29 serpin encoding genes. Amino acid sequence analysis has placed 14 of these serpins in serpin clade Q and 3 in serpin clade K with the remaining 12 serpins classified as orphan serpins not belonging to any clade.[182] 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 Drosphila serpin genes on the Drosophila chromosomes. 13 of the Drosophila serpins occur as isolated genes in the genome (including Serpin-27A, see below), with the remaining 16 organised into three gene clusters that occur at chromosome positions 28D (2 serpins), 42D (5 serpins), 43A (4 serpins), 77B (3 serpins) and 88E (2 serpins).[182][183][184]

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 Spätzle (a chemokine-type ligand), which results in Toll mediated signaling. In addition to its central role in embryonic patterning, Toll signaling is also important for the innate immune response in insects. Accordingly, serpin-27A additionally functions to control the insect immune response.[185][186][187] In Tenebrio molitor (a large beetle), a protein (SPN93) comprising two discrete tandem serpin domains functions to regulate the toll proteolytic cascade.[188]


The genome of the nematode worm C. elegans contains nine serpins, however, only five of these molecules appear to function as protease inhibitors.[30] One of these serpins, SRP-6, has been shown to perform a protective function and guard against stress induced calpain-associated lysosomal disruption. Further SRP-6 functions to inhibit 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). Based on these data it is suggested that lysosomes play a general and controllable role in determining cell fate.[189]


The presence of serpins in plants has long been recognised,[190] indeed, an abundant barley grain serpin (barley Protein Z) is one of the major protein components in beer.

The MEROPS database identifies 18 serpin family members in the Arabidopsis thaliana genome, but only about eight of these are full-length serpin sequences. Plant serpins are potent inhibitors of mammalian chymotrypsin-like serine proteases in vitro, the most well-studied example being barley serpin Zx (BSZx), which is able to inhibit trypsin, chymotrypsin as well as several blood coagulation factors.[191] However, close relatives of chymotrypsin-like serine proteases are absent in plants. The RCL of several serpins from wheat grain and rye [192] contain poly-Q repeat sequences similar to those present in the prolamin storage proteins of the endosperm.[193] It has therefore been suggested that plant serpins may function to inhibit proteases from insects or microbes that cleave grain storage proteins. In support of this hypothesis, specific plant serpins have been identified in the phloem sap of pumpkin (CmPS-1)[194] and cucumber plants.[195][196] However, while 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.[194]

Alternative roles and protease targets for plant serpins have been proposed. It has been shown that Arabidopsis AtSerpin1 (At1g47710; 3LE2[24]) inhibits metacaspase-like proteases in vitro.[23] More recently, the major in vivo protease target for AtSerpin1 was identified as the papain-like cysteine protease RESPONSIVE TO DESICCATION-21 (RD21). Through this activity, AtSerpin1 was shown to exert set-point control over programmed cell death in Arabidopsis.[197]

Two other Arabidopsis serpins, AtSRP2 (At2g14540) and AtSRP3 (At1g64030) appear to be involved in responses to DNA damage caused by plant exposure to methane methylsulfonate (MMS).[198]


A single fungal serpin has been characterized to date: celpin from Piromyces sp. strain E2. Piromyces is an anaerobic fungus found in the gut of ruminants and is important for digesting plant material. Celpin is predicted to be an inhibitory molecule and contains two N-terminal dockerin domains in addition to the serpin domain. Dockerins are commonly found in proteins that localise to the fungal cellulosome, a large extracellular multiprotein complex that breaks down cellulose.[8] It is therefore suggested that celpin protects the cellulosome against plant proteases. Certain bacterial serpins also localize to the cellulosome.[199]


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 molecule possess elevated resistance to heat denaturation.[200][201] The precise role of most bacterial serpins remains obscure, however, 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.[199]


Serpins are also expressed by viruses as a way to evade the host's immune defense.[202] 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.[203][204] A study on Serp1 reveals this molecule suppresses the Toll-mediated innate immune response and allows indefinite cardiac allograft survival in rats.[203][205] Studies on Crma and Serp2, reveal both are cross-class inhibitor and targets both serine (Granzyme B; albeit weakly) and cysteine proteases (Caspase 1 and Caspase 8).[206][207] In comparison to their mammalian counterparts, viral serpins contain significant deletions of elements of secondary structure. Specifically, structural studies on crmA reveals this molecule lacks the D-helix as well as significant portions of the A- and E-helices.[208]

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  146. ^ Bruce D, Perry DJ, Borg JY, Carrell RW, Wardell MR. (1994). "Thromboembolic disease due to thermolabile conformational changes of antithrombin Rouen-VI (187 Asn-->Asp)". J. Clin. Invest. 94 (6): 2265–74. doi:10.1172/JCI117589. PMC 330053. PMID 7989582. 
  147. ^ Baglin TP, Carrell RW, Church FC, Esmon CT, Huntington JA (2002). "Crystal structures of native and thrombin-complexed heparin cofactor II reveal a multistep allosteric mechanism". Proc. Natl. Acad. Sci. U.S.A. 99 (17): 11079–84. doi:10.1073/pnas.162232399. PMC 123213. PMID 12169660. 
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  154. ^ Bajou K, Peng H, Laug WE; et al. (October 2008). "Plasminogen Activator Inhibitor-1 Protects Endothelial Cells from FasL-Mediated Apoptosis". Cancer Cell 14 (4): 324–34. doi:10.1016/j.ccr.2008.08.012. PMC 2630529. PMID 18835034. 
  155. ^ Li W, Huntington JA (May 2012). "Crystal structures of protease nexin-1 in complex with heparin and thrombin suggest a two-step recognition mechanism". Blood 120 (2): 459–67. doi:10.1182/blood-2012-03-415869. PMID 22618708. 
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  172. ^ Christiansen HE, Schwarze U, Pyott SM, AlSwaid A, Al Balwi M, Alrasheed S, Pepin MG, Weis MA, Eyre DR, Byers PH (March 2010). "Homozygosity for a Missense Mutation in SERPINH1, which Encodes the Collagen Chaperone Protein HSP47, Results in Severe Recessive Osteogenesis Imperfecta". American Journal of Human Genetics 86 (3): 389–98. doi:10.1016/j.ajhg.2010.01.034. PMC 2833387. PMID 20188343. 
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  174. ^ Takehara S, Onda M, Zhang J, Nishiyama M, Yang X, Mikami B, Lomas DA (March 2009). "2.1A Crystal Structure of Native Neuroserpin Reveals Unique Structural Elements that Contribute to Conformational Instability". J. Mol. Biol. 388 (1): 11–20. doi:10.1016/j.jmb.2009.03.007. PMID 19285087. 
  175. ^ Ricagno S, Caccia S, Sorrentino G, Antonini G, Bolognesi M (March 2009). "Human Neuroserpin; Structure and Time-dependent Inhibition". J. Mol. Biol. 388 (1): 109–21. doi:10.1016/j.jmb.2009.02.056. PMID 19265707. 
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  177. ^ Davis RL, Shrimpton AE, Holohan PD, Bradshaw C, Feiglin D, Collins GH, Sonderegger P, Kinter J, Becker LM, Lacbawan F, Krasnewich D, Muenke M, Lawrence DA, Yerby MS, Shaw CM, Gooptu B, Elliott PR, Finch JT, Carrell RW, Lomas DA. (1999). "Familial dementia caused by polymerization of mutant neuroserpin". Nature 401 (6751): 376–9. doi:10.1038/43894. PMID 10517635. 
  178. ^ a b Ozaki K, Nagata M, Suzuki M, Fujiwara T, Miyoshi Y, Ishikawa O, Ohigashi H, Imaoka S, Takahashi E, Nakamura Y. (1998). "Isolation and characterization of a novel human pancreas-specific gene, pancpin, that is down-regulated in pancreatic cancer cells". Genes Chromosomes and Cancer 22 (3): 179–85. doi:10.1002/(SICI)1098-2264(199807)22:3<179::AID-GCC3>3.0.CO;2-T. PMID 9624529. 
  179. ^ Loftus SK, Cannons JL, Incao A, Pak E, Chen A, Zerfas PM, Bryant MA, Biesecker LG, Schwartzberg PL, Pavan WJ (2005). "Acinar Cell Apoptosis in Serpini2-Deficient Mice Models Pancreatic Insufficiency". PLoS. Genet. 1 (3): e38. doi:10.1371/journal.pgen.0010038. PMC 1231717. PMID 16184191. 
  180. ^ Padua MB, Kowalski AA, Cañas MY, Hansen PJ (February 2010). "The molecular phylogeny of uterine serpins and its relationship to evolution of placentation". FASEB J. 24 (2): 526–37. doi:10.1096/fj.09-138453. PMID 19825977. 
  181. ^ Padua MB, Hansen PJ (October 2010). "Evolution and function of the uterine serpins (SERPINA14)". Am. J. Reprod. Immunol. 64 (4): 265–74. doi:10.1111/j.1600-0897.2010.00901.x. PMID 20678169. 
  182. ^ a b Reichhart JM. (2005). "Tip of another iceberg: Drosophila serpins". Trends Cell Biol. 15 (12): 659–665. doi:10.1016/j.tcb.2005.10.001. PMID 16260136. 
  183. ^ 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): 617–26. doi:10.1016/j.devcel.2008.08.017. PMC 2671232. PMID 18854145. 
  184. ^ Scherfer C, Tang H, Kambris Z, Lhocine N, Hashimoto C, Lemaitre B (September 2008). "Drosophila Serpin-28D regulates hemolymph phenoloxidase activity and adult pigmentation". Developmental biology 323 (2): 189–96. doi:10.1016/j.ydbio.2008.08.030. PMID 18801354. 
  185. ^ Rushlow C (2004). "Dorsoventral patterning: a serpin pinned down at last". Curr. Biol. 14 (1): R16–8. doi:10.1016/j.cub.2003.12.015. PMID 14711428. 
  186. ^ Ligoxygakis P, Roth S, Reichhart JM (2003). "A serpin regulates dorsal-ventral axis formation in the Drosophila embryo". Curr. Biol. 13 (23): 2097–102. doi:10.1016/j.cub.2003.10.062. PMID 14654000. 
  187. ^ Hashimoto C, Kim DR, Weiss LA, Miller JW, Morisato D (2003). "Spatial regulation of developmental signaling by a serpin". Dev. Cell 5 (6): 945–50. doi:10.1016/S1534-5807(03)00338-1. PMID 14667416. 
  188. ^ Jiang R, Zhang B, Kurokawa K; et al. (August 2011). "93-kDa Twin-domain Serine Protease Inhibitor (Serpin) Has a Regulatory Function on the Beetle Toll Proteolytic Signaling Cascade". J Biol Chem 286 (40): 35087–95. doi:10.1074/jbc.M111.277343. PMC 3186399. PMID 21862574. 
  189. ^ Cliff J. Luke, Stephen C. Pak, Yuko S. Askew, Terra L. Naviglia, David J. Askew, Shila M. Nobar, Anne C. Vetica, Olivia S. Long, Simon C. Watkins, Donna B. Stolz, Robert J. Barstead, Gary L. Moulder, Dieter Brömme, and Gary A. Silverman (2007). "An Intracellular Serpin Regulates Necrosis by Inhibiting the Induction and Sequelae of Lysosomal Injury". Cell 130 (6): 1108–1119. doi:10.1016/j.cell.2007.07.013. PMC 2128786. PMID 17889653. 
  190. ^ 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): 89–94. doi:10.1016/0014-5793(85)80238-6. 
  191. ^ Dahl SW, Rasmussen SK, Peterson LC, Hejgaard J. (1996). "Inhibition of coagulation factors by recombinant barley serpin BSZx". FEBS Lett. 394 (2): 165–8. doi:10.1016/0014-5793(96)00940-4. PMID 8843156. 
  192. ^ Hejgaard J. (2001). "Inhibitory serpins from rye grain with glutamine as P1 and P2 residues in the reactive center". FEBS Lett. 488 (3): 149–53. doi:10.1016/S0014-5793(00)02425-X. PMID 11163762. 
  193. ^ Ostergaard H, Rasmussen SK, Roberts TH, Hejgaard J. (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". J Biol Chem. 275 (43): 33272–9. doi:10.1074/jbc.M004633200. PMID 10874043. 
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  195. ^ la Cour Petersen M, Hejgaard J, Thompson GA, Schulz A. (2005). "Cucurbit phloem serpins are graft-transmissible and appear to be resistant to turnover in the sieve element-companion cell complex". J Exp Bot. 56 (422): 3111–20. doi:10.1093/jxb/eri308. PMID 16246856. 
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  199. ^ a b Kang S, Barak Y, Lamed R, Bayer EA, Morrison M. (2006). "The functional repertoire of prokaryote cellulosomes includes the serpin superfamily of serine proteinase inhibitors". Mol Microbiol. 60 (6): 1344–54. doi:10.1111/j.1365-2958.2006.05182.x. PMID 16796673. 
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  201. ^ Fulton KF, Buckle AM, Cabrita LD, Irving JA, Butcher RE, Smith I, Reeve S, Lesk AM, Bottomley SP, Rossjohn J, Whisstock JC. (2005). "The high resolution crystal structure of a native thermostable serpin reveals the complex mechanism underpinning the stressed to relaxed transition". J Biol Chem. 280 (9): 8435–42. doi:10.1074/jbc.M410206200. PMID 15590653. 
  202. ^ Turner PC, Moyer RW (2002). "Poxvirus immune modulators: functional insights from animal models". Virus Res. 88 (1–2): 35–53. doi:10.1016/S0168-1702(02)00119-3. PMID 12297326. 
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  204. ^ Jiang J, Arp J, Kubelik D, Zassoko R, Liu W, Wise Y, Macaulay C, Garcia B, McFadden G, Lucas AR, Wang H (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): 1158–67. doi:10.1097/ PMID 17998872. (subscription required (help)). 
  205. ^ Dai E, Guan H, Liu L, Little S, McFadden G, Vaziri S, Cao H, Ivanova IA, Bocksch L, Lucas A (2003). "Serp-1, a viral anti-inflammatory serpin, regulates cellular serine proteinase and serpin responses to vascular injury". J. Biol. Chem. 278 (20): 18563–72. doi:10.1074/jbc.M209683200. PMID 12637546. 
  206. ^ Turner PC, Sancho MC, Thoennes SR, Caputo A, Bleackley RC, Moyer RW (1999). "Myxoma Virus Serp2 Is a Weak Inhibitor of Granzyme B and Interleukin-1β-Converting Enzyme In Vitro and Unlike CrmA Cannot Block Apoptosis in Cowpox Virus-Infected Cells". J. Virol. 73 (8): 6394–404. PMC 112719. PMID 10400732. 
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External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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.

Literature references

  1. Wright HT; , Bioessays 1996;18:453-464.: The structural puzzle of how serpin serine proteinase inhibitors work. PUBMED:8787534 EPMC:8787534

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.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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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, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

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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.

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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.

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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

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...


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.

Curation View help on the curation process

Seed source: Overington and HMM_iterative_training
Previous IDs: serpin;
Type: Domain
Author: Eddy SR
Number in seed: 131
Number in full: 4827
Average length of the domain: 302.40 aa
Average identity of full alignment: 23 %
Average coverage of the sequence by the domain: 85.05 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 11927849 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 21.8 21.8
Trusted cut-off 21.8 21.8
Noise cut-off 21.4 21.7
Model length: 370
Family (HMM) version: 17
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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The tree shows the occurrence of this domain across different species. More...


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There are 7 interactions for this family. More...

Trypsin Trypsin Asp Thrombin_light Somatomedin_B Asp Serpin


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 369 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 seqence.

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