Summary: Integrin alpha cytoplasmic region
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Integrin Edit Wikipedia article
|Integrin alphavbeta3 extracellular domains|
Structure of the extracellular segment of integrin alpha Vbeta3.
|Integrin alpha cytoplasmic region|
Structure of chaperone protein PAPD.
|Integrin, beta chain|
|Integrin beta 7 cytoplasmic domain: complex with filamin|
crystal structure of the filamin a repeat 21 complexed with the integrin beta7 cytoplasmic tail peptide
Integrins are transmembrane receptors that are the bridges for cell-cell and cell-extracellular matrix (ECM) interactions. When triggered, integrins in turn trigger chemical pathways to the interior (signal transduction), such as the chemical composition and mechanical status of the ECM, which results in a response (activation of transcription) such as regulation of the cell cycle, cell shape, and/or motility; or new receptors being added to the cell membrane. This allows rapid and flexible responses to events at the cell surface, for example to signal platelets to initiate an interaction with coagulation factors.
There are several types of integrins, and a cell may have several types on its surface. Integrins are found in all metazoa.
Integrins work alongside other receptors such as cadherins, the immunoglobulin superfamily cell adhesion molecules, selectins and syndecans to mediate cell–cell and cell–matrix interaction. Ligands for integrins include fibronectin, vitronectin, collagen, and laminin.
Integrins are obligate heterodimers, meaning that they have two different chains: the α (alpha) and β (beta) subunits. In mammals, there are eighteen α and eight β subunits, in Drosophila five α and two β subunits, and in Caenorhabditis nematodes two α subunits and one β subunit. The α and β subunits each penetrate the plasma membrane and possess small cytoplasmic domains.
Variants of some of the subunits are formed by differential RNA splicing; for example, four variants of the beta-1 subunit exist. Through different combinations of the α and β subunits, around 24 unique integrins are generated. (See Vertebrate integrins below)
Integrin subunits span the cell membrane and have short cytoplasmic domains of 40–70 amino acids. The exception is the beta-4 subunit, which has a cytoplasmic domain of 1088 amino acids, one of the largest known cytoplasmic domains of any membrane protein. Outside the cell membrane, the α and β chains lie close together along a length of about 23 nm; the final 5 nm N-termini of each chain forms a ligand-binding region for the ECM. They have been compared to lobster claws, although the don't actually "pinch" their ligand, they chemically interact with it at the insides of the "tips" of their "pinchers".
The molecular mass of the integrin subunits can vary from 90 kDa to 160 kDa. Beta subunits have four cysteine-rich repeated sequences. Both α and β subunits bind several divalent cations. The role of divalent cations in the α subunit is unknown, but may stabilize the folds of the protein. The cations in the β subunits are more interesting: they are directly involved in coordinating at least some of the ligands that integrins bind.
There are various ways of categorizing the integrins. For example, a subset of the α chains has an additional structural element (or "domain") inserted toward the N-terminal, the alpha-A domain (so called because it has a similar structure to the A-domains found in the protein von Willebrand factor; it is also termed the α-I domain). Integrins carrying this domain either bind to collagens (e.g. integrins α1 β1, and α2 β1), or act as cell-cell adhesion molecules (integrins of the β2 family). This α-I domain is the binding site for ligands of such integrins. Those integrins that don't carry this inserted domain also have an A-domain in their ligand binding site, but this A-domain is found on the β subunit.
In both cases, the A-domains carry up to three divalent cation binding sites. One is permanently occupied in physiological concentrations of divalent cations, and carries either a calcium or magnesium ion, the principal divalent cations in blood at median concentrations of 1.4 mM (calcium) and 0.8 mM (magnesium). The other two sites become occupied by cations when ligands bind—at least for those ligands involving an acidic amino acid in their interaction sites. An acidic amino acid features in the integrin-interaction site of many ECM proteins, for example as part of the amino acid sequence Arginine-Glycine-Aspartic acid ("RGD" in the one-letter amino acid code).
Despite many years of effort, discovering the high-resolution structure of integrins proved to be challenging: membrane proteins are classically difficult to purify, and integrins are also large, complex and linked to many sugar trees ("highly glycosylated"). Low-resolution images of detergent extracts of intact integrin GPIIbIIIa, obtained using electron microscopy, and even data from indirect techniques that investigate the solution properties of integrins using ultracentrifugation and light scattering, were combined with fragmentary high-resolution crystallographic or NMR data from single or paired domains of single integrin chains, and molecular models postulated for the rest of the chains.
Despite these wide-ranging efforts, the X-ray crystal structure obtained for the complete extracellular region of one integrin, αvβ3, determined in 2001 by the laboratory of Dr. M. Amin Arnaout, MD, at Massachusetts General Hospital and Harvard Medical School, was a surprise. It showed the molecule to be folded into an inverted V-shape that potentially brings the ligand-binding sites close to the cell membrane. Perhaps more importantly, the crystal structure was also obtained for the same integrin bound to a small ligand containing the RGD-sequence, the drug cilengitide. As detailed above, this finally revealed why divalent cations (in the A-domains) are critical for RGD-ligand binding to integrins. The interaction of such sequences with integrins is believed to be a primary switch by which ECM exerts its effects on cell behaviour.
The structure poses many questions, especially regarding ligand binding and signal transduction. The ligand binding site is directed towards the C-terminal of the integrin, the region where the molecule emerges from the cell membrane. If it emerges orthogonally from the membrane, the ligand binding site would apparently be obstructed, especially as integrin ligands are typically massive and well cross-linked components of the ECM. In fact, little is known about the angle that membrane proteins subtend to the plane of the membrane; this is a problem difficult to address with available technologies. The default assumption is that they emerge rather like little lollipops, but the evidence for this sweet supposition is noticeable by its absence. The integrin structure has drawn attention to this problem, which may have general implications for how membrane proteins work. It appears that the integrin transmembrane helices are tilted (see "Activation" below), which hints that the extracellular chains may also not be orthogonal with respect to the membrane surface.
Although the crystal structure changed surprisingly little after binding to cilengitide, the current hypothesis is that integrin function involves changes in shape to move the ligand-binding site into a more accessible position, away from the cell surface, and this shape change also triggers intracellular signaling. There is a wide body of cell-biological and biochemical literature that supports this view. Perhaps the most convincing evidence involves the use of antibodies that only recognize integrins when they have bound to their ligands, or are activated. As the "footprint" that an antibody makes on its binding target is roughly a circle about 3 nm in diameter, the resolution of this technique is low. Nevertheless, these so-called LIBS (Ligand-Induced-Binding-Sites) antibodies unequivocally show that dramatic changes in integrin shape routinely occur. However, how the changes detected with antibodies look on the structure is still unknown.
When released into the cell membrane, newly synthesized integrin dimers are speculated to be found in the same "bent" conformation revealed by the structural studies described above. One school of thought claims that this bent form prevents them from interacting with their ligands, although bent forms can predominate in high-resolution EM structures of integrin bound to an ECM ligand. Therefore, at least in biochemical experiments, integrin dimers must apparently not be 'unbent' in order to prime them and allow their binding to the ECM. In cells, the priming is accomplished by a protein talin, which binds to the β tail of the integrin dimer and changes its conformation. The α and β integrin chains are both class-I transmembrane proteins: they pass the plasma membrane as single transmembrane alpha-helices. Unfortunately, the helices are too long, and recent studies suggest that, for integrin gpIIbIIIa, they are tilted with respect both to one another and to the plane of the membrane. Talin binding alters the angle of tilt of the β3 chain transmembrane helix in model systems and this may reflect a stage in the process of inside-out signalling which primes integrins. Moreover, talin proteins are able to dimerize and thus are thought to intervene in the clustering of integrin dimers which leads to the formation of a focal adhesion. Recently, the Kindlin-1 and Kindlin-2 proteins have also been found to interact with integrin and activate it.
Integrins have two main functions:-
- Attachment of the cell to the ECM
- Signal transduction from the ECM to the cell
However, they are also involved in a wide range of other biological activities, including immune patrolling, cell migration, and binding to cells by certain viruses, such as adenovirus, echovirus, hantavirus, and foot and mouth disease viruses.
A prominent function of the integrins is seen in the molecule GPIIbIIIa, an integrin on the surface of blood platelets (thrombocytes) responsible for attachment to fibrin within a developing blood clot. This molecule dramatically increases its binding affinity for fibrin/fibrinogen through association of platelets with exposed collagens in the wound site. Upon association of platelets with collagen, GPIIbIIIa changes shape, allowing it to bind to fibrin and other blood components to form the clot matrix and stop blood loss.
Attachment of cell to the ECM
Integrins couple the ECM outside a cell to the cytoskeleton (in particular, the microfilaments) inside the cell. Which ligand in the ECM the integrin can bind to is defined by which α and β subunits the integrin is made of. Among the ligands of integrins are fibronectin, vitronectin, collagen, and laminin. The connection between the cell and the ECM may help the cell to endure pulling forces without being ripped out of the ECM. The ability of a cell to create this kind of bond is also of vital importance in ontogeny.
Cell attachment to the ECM is a basic requirement to build a multicellular organism. Integrins are not simply hooks, but give the cell critical signals about the nature of its surroundings. Together with signals arising from receptors for soluble growth factors like VEGF, EGF, and many others, they enforce a cellular decision on what biological action to take, be it attachment, movement, death, or differentiation. Thus integrins lie at the heart of many cellular biological processes. The attachment of the cell takes place through formation of cell adhesion complexes, which consist of integrins and many cytoplasmic proteins, such as talin, vinculin, paxillin, and alpha-actinin. These act by regulating kinases such as FAK (focal adhesion kinase) and Src kinase family members to phosphorylate substrates such as p130CAS thereby recruiting signaling adaptors such as CRK. These adhesion complexes attach to the actin cytoskeleton. The integrins thus serve to link two networks across the plasma membrane: the extracellular ECM and the intracellular actin filamentous system. Integrin alpha6beta4 is an exception: it links to the keratin intermediate filament system in epithelial cells.
Focal adhesions are large molecular complexes, which are generated following interaction of integrins with ECM, then their clustering. The clusters likely provide sufficient intracellular binding sites to permit the formation of stable signaling complexes on the cytoplasmic side of the cell membrane. So the focal adhesions contain integrin ligand, integrin molecule, and associate plaque proteins. Binding is propelled by changes in free energy. As previously stated, these complexes connect the extracellular matrix to actin bundles. Cryo-electron tomography reveals that the adhesion contains particles on the cell membrane with diameter of 25 +/- 5 nm and spaced at approximately 45 nm. Treatment with Rho-kinase inhibitor Y-27632 reduces the size of the particle, and it is extremely mechanosensitive.
One important function of integrins on cells in tissue culture is their role in cell migration. Cells adhere to a substrate through their integrins. During movement, the cell makes new attachments to the substrate at its front and concurrently releases those at its rear. When released from the substrate, integrin molecules are taken back into the cell by endocytosis; they are transported through the cell to its front by the endocytic cycle, where they are added back to the surface. In this way they are cycled for reuse, enabling the cell to make fresh attachments at its leading front. It is not yet clear whether cell migration in tissue culture is an artefact of integrin processing, or whether such integrin-dependent cell migration also occurs in living organisms.
Integrins play an important role in cell signaling by modulating the cell signaling pathways of transmembrane protein kinases such as receptor tyrosine kinases (RTK). While the interaction between integrin and receptor tyrosine kinases originally was thought of as uni-directional and supportive, recent studies indicate that integrins have additional, multi-faceted roles in cell signaling. Integrins can regulate the receptor tyrosine kinase signaling by recruiting specific adaptors to the plasma membrane. For example, β1c integrin recruits Gab1/Shp2 and presents Shp2 to IGF1R, resulting in dephosphorylation of the receptor. In a reverse direction, when a receptor tyrosine kinase is activated, integrins co-localise at focal adhesion with the receptor tyrosine kinases and their associated signaling molecules.
The repertoire of integrins expressed on a particular cell can specify the signaling pathway due to the differential binding affinity of ECM ligands for the integrins. The tissue stiffness and matrix composition can initiate specific signaling pathways regulating cell behavior. Clustering and activation of the integrins/actin complexes strengthen the focal adhesion interaction and initiate the framework for cell signaling through assembly of adhesomes.
Depending on the integrin's regulatory impact on specific receptor tyrosine kinases, the cell can experience:
- cell growth,
- cell division,
- cell survival,
- cellular differentiation, and
- apoptosis (programmed cell death).
Knowledge of the relationship between integrins and receptor tyrosine kinase has laid a foundation for new approaches to cancer therapy. Specifically, targeting integrins associated with RTKs is an emerging approach for inhibiting angiogenesis.
The following are 16 of the ~24 integrins found in vertebrates:
|α4β1||VLA-4||Hematopoietic cells||Fibronectin, VCAM-1|
|α5β1||VLA-5; fibronectin receptor||widespread||fibronectin and proteinases|
|α6β1||VLA-6; laminin receptor||widespread||laminins|
|αMβ2||Mac-1, CR3||Neutrophils and monocytes||Serum proteins, ICAM-1|
|αIIbβ3||Fibrinogen receptor; gpIIbIIIa||Platelets||fibrinogen, fibronectin|
|αVβ1||ocular melanoma; neurological tumors||vitronectin; fibrinogen|
|αVβ3||vitronectin receptor||activated endothelial cells, melanoma, glioblastoma||vitronectin, fibronectin, fibrinogen, osteopontin, Cyr61|
|αVβ5||widespread, esp. fibroblasts, epithelial cells||vitronectin and adenovirus|
|αVβ6||proliferating epithelia, esp. lung and mammary gland||fibronectin; TGFβ1+3|
|αVβ8||neural tissue; peripheral nerve||fibronectin; TGFβ1+3|
Beta-1 integrins interact with many alpha integrin chains. Gene knockouts of integrins in mice are not always lethal, which suggests that during embryonal development, one integrin may substitute its function for another in order to allow survival. Some integrins are on the cell surface in an inactive state, and can be rapidly primed, or put into a state capable of binding their ligands, by cytokines. Integrins can assume several different well-defined shapes or "conformational states". Once primed, the conformational state changes to stimulate ligand binding, which then activates the receptors — also by inducing a shape change — to trigger outside-in signal transduction.
- Xiong JP, Stehle T, Diefenbach B, Zhang R, Dunker R, Scott DL, Joachimiak A, Goodman SL, Arnaout MA (2001). "Crystal structure of the extracellular segment of integrin alpha Vbeta3". Science 294 (5541): 339–45. doi:10.1126/science.1064535. PMC 2885948. PMID 11546839.
- Sauer FG, Fütterer K, Pinkner JS, Dodson KW, Hultgren SJ, Waksman G. "Structural basis of chaperone function and pilus biogenesis". Science 285 (5430): 1058–61. doi:10.1126/science.285.5430.1058. PMID 10446050.
- Hynes RO (2002). "Integrins: bidirectional, allosteric signaling machines". Cell 110 (6): 673–87. doi:10.1016/s0092-8674(02)00971-6. PMID 12297042.
- Humphries MJ (2000). "Integrin structure". Biochem. Soc. Trans. 28 (4): 311–339. doi:10.1042/0300-5127:0280311. PMID 10961914.
- Nermut MV, Green NM, Eason P, Yamada SS, Yamada KM (December 1988). "Electron microscopy and structural model of human fibronectin receptor". EMBO J. 7 (13): 4093–9. PMC 455118. PMID 2977331.
- Hynes RO (2002). "Integrins: bidirectional, allosteric signaling machines". Cell 110 (6): 673–87. doi:10.1016/S0092-8674(02)00971-6. PMID 12297042.
- Xiong JP, Stehle T, Diefenbach B, Zhang R, Dunker R, Scott DL, Joachimiak A, Goodman SL, Arnaout MA (2001). "Crystal structure of the extracellular segment of integrin αvβ3". Science 294 (5541): 339–345. doi:10.1126/science.1064535. PMC 2885948. PMID 11546839.
- Smith JW (2003). "Cilengitide Merck". Curr Opin Investig Drugs 4 (6): 741–5. PMID 12901235.
- Calderwood DA (June 2004). "Talin controls integrin activation". Biochem. Soc. Trans. 32 (Pt3): 434–7. doi:10.1042/BST0320434. PMID 15157154.
- Calderwood DA, Zent R, Grant R, Rees DJ, Hynes RO, Ginsberg MH (October 1999). "The Talin head domain binds to integrin beta subunit cytoplasmic tails and regulates integrin activation". J. Biol. Chem. 274 (40): 28071–4. doi:10.1074/jbc.274.40.28071. PMID 10497155.
- Shattil SJ, Kim C, Ginsberg MH (2010). "The final steps of integrin activation: the end game". Nature Reviews Molecular Cell Biology 11 (4): 288–300. doi:10.1038/nrm2871. PMID 20308986.
- Goldmann WH, Bremer A, Häner M, Aebi U, Isenberg G (1994). "Native talin is a dumbbell-shaped homodimer when it interacts with actin". J. Struct. Biol. 112 (1): 3–10. doi:10.1006/jsbi.1994.1002. PMID 8031639.
- Harburger DS, Bouaouina M, Calderwood DA (April 2009). "Kindlin-1 and −2 directly bind the C-terminal region of beta integrin cytoplasmic tails and exert integrin-specific activation effects". J. Biol. Chem. 284 (17): 11485–97. doi:10.1074/jbc.M809233200. PMC 2670154. PMID 19240021.
- Olberding JE, Thouless MD, Arruda EM, Garikipati K (2010). Buehler MJ, ed. "The non-equilibrium thermodynamics and kinetics of focal adhesion dynamics". PLoS ONE 5 (8): e12043. doi:10.1371/journal.pone.0012043. PMC 2923603. PMID 20805876.
- Patla I, Volberg T, Elad N, Hirschfeld-Warneken V, Grashoff C, Fässler R, Spatz JP, Geiger B, Medalia O (September 2010). "Dissecting the molecular architecture of integrin adhesion sites by cryo-electron tomography". Nat. Cell Biol. 12 (9): 909–15. doi:10.1038/ncb2095. PMID 20694000.
- Gullingsrud J, Sotomayor M. "Mechanosensitive channels". Theoretical and Computational Biophysics Group, Beckman Institute for Advanced Science and Technology: University of Illinois at Urbana-Champaign.
- Goel HL, Breen M, Zhang J, Das I, Aznavoorian-Cheshire S, Greenberg NM, Elgavish A, Languino LR (1 August 2005). "1A Integrin Expression Is Required for Type 1 Insulin-Like Growth Factor Receptor Mitogenic and Transforming Activities and Localization to Focal Contacts". Cancer Research 65 (15): 6692–6700. doi:10.1158/0008-5472.CAN-04-4315. PMID 16061650.
- Kim SH, Turnbull J, Guimond S (2011). "Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor". J. Endocrinol. 209 (2): 139–51. doi:10.1530/JOE-10-0377. PMID 21307119.
- Carbonell WS, DeLay M, Jahangiri A, Park CC, Aghi MK (3 May 2013). "1 Integrin Targeting Potentiates Antiangiogenic Therapy and Inhibits the Growth of Bevacizumab-Resistant Glioblastoma". Cancer Research 73 (10): 3145–3154. doi:10.1158/0008-5472.CAN-13-0011. PMC 4040366. PMID 23644530.
- Krieger M, Scott MP, Matsudaira PT, Lodish HF, Darnell JE, Zipursky L, Kaiser C, Berk A (2004). Molecular cell biology (fifth ed.). New York: W.H. Freeman and CO. ISBN 0-7167-4366-3.
- Elangbam CS, Qualls CW, Dahlgren RR (1997). "Cell adhesion molecules--update" (PDF). Vet. Pathol. 34 (1): 61–73. doi:10.1177/030098589703400113. PMID 9150551.
- Hermann P, Armant M, Brown E, Rubio M, Ishihara H, Ulrich D, Caspary RG, Lindberg FP, Armitage R, Maliszewski C, Delespesse G, Sarfati M (February 1999). "The vitronectin receptor and its associated CD47 molecule mediates proinflammatory cytokine synthesis in human monocytes by interaction with soluble CD23". J. Cell Biol. 144 (4): 767–75. doi:10.1083/jcb.144.4.767. PMC 2132927. PMID 10037797.
Media related to Integrins at Wikimedia Commons
- MBInfo - Integrin-Mediated Signalling
- MBInfo - Integrin Activation
- Eukaryotic Linear Motif resource motif class LIG_RGD
- Eukaryotic Linear Motif resource motif class LIG_Integrin_isoDGR_1
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- Talin substrate for calpain – PMAP The Proteolysis Map animation.
- Integrins at the US National Library of Medicine Medical Subject Headings (MeSH)
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.
Integrin alpha cytoplasmic region Provide feedback
This family contains the short intracellular region of integrin alpha chains.
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This tab holds annotation information from the InterPro database.
InterPro entry IPR018184Some alpha subunits are cleaved post- translationally to produce a heavy and a light chain linked by a disulphide bond [PUBMED:3028640, PUBMED:2199285]. Integrin alpha chains share a conserved sequence which is found at the beginning of the cytoplasmic domain, just after the end of the transmembrane region. Within the N-terminal domain of alpha subunits, seven sequence repeats, each of approximately 60 amino acids, have been found [PUBMED:3327687]. It has been predicted that these repeats assume the beta-propeller fold. The domains contain seven four-stranded beta-sheets arranged in a torus around a pseudosymmetry axis [PUBMED:8990162]. Integrin ligands and a putative Mg2+ ion are predicted to bind to the upper face of the propeller, in a manner analogous to the way in which the trimeric G-protein beta subunit (G beta) (which also has a beta-propeller fold) binds the G protein alpha subunit [PUBMED:8990162].
Integrin cytoplasmic domains are normally less than 50 amino acids in length, with the beta-subunit sequences exhibiting greater homology to each other than the alpha-subunit sequences [PUBMED:12826403]. This is consistent with current evidence that the beta subunit is the principal site for binding of cytoskeletal and signalling molecules, whereas the alpha subunit has a regulatory role. The first ten residues of the alpha-subunit cytoplasmic domain appear to form an alpha helix that is terminated by a proline residue. The remainder of the domain is highly acidic in nature and this loops back to contact the membrane-proximal lysine anchor residue.
This entry represents the conserved site of the C-terminal integrin alpha chain.
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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|Author:||Bateman A, Finn RD|
|Number in seed:||24|
|Number in full:||369|
|Average length of the domain:||14.90 aa|
|Average identity of full alignment:||52 %|
|Average coverage of the sequence by the domain:||1.47 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 11927849 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||17|
|Download:||download the raw HMM for this family|
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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.
There are 2 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
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 Integrin_alpha domain has been found. There are 15 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.
Loading structure mapping...