| Structural highlights
4g1e is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , , |
| Gene: | ITGAV, MSK8, VNRA (Homo sapiens), ITGB3, GP3A (Homo sapiens) |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Disease
[ITB3_HUMAN] Defects in ITGB3 are a cause of Glanzmann thrombasthenia (GT) [MIM:273800]; also known as thrombasthenia of Glanzmann and Naegeli. GT is the most common inherited disease of platelets. It is an autosomal recessive disorder characterized by mucocutaneous bleeding of mild-to-moderate severity and the inability of this integrin to recognize macromolecular or synthetic peptide ligands. GT has been classified clinically into types I and II. In type I, platelets show absence of the glycoprotein IIb/beta-3 complexes at their surface and lack fibrinogen and clot retraction capability. In type II, the platelets express the glycoprotein IIb/beta-3 complex at reduced levels (5-20% controls), have detectable amounts of fibrinogen, and have low or moderate clot retraction capability. The platelets of GT 'variants' have normal or near normal (60-100%) expression of dysfunctional receptors.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]
Function
[ITAV_HUMAN] The alpha-V integrins are receptors for vitronectin, cytotactin, fibronectin, fibrinogen, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin and vWF. They recognize the sequence R-G-D in a wide array of ligands. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions. [ITB3_HUMAN] Integrin alpha-V/beta-3 is a receptor for cytotactin, fibronectin, laminin, matrix metalloproteinase-2, osteopontin, osteomodulin, prothrombin, thrombospondin, vitronectin and von Willebrand factor. Integrin alpha-IIb/beta-3 is a receptor for fibronectin, fibrinogen, plasminogen, prothrombin, thrombospondin and vitronectin. Integrins alpha-IIb/beta-3 and alpha-V/beta-3 recognize the sequence R-G-D in a wide array of ligands. Integrin alpha-IIb/beta-3 recognizes the sequence H-H-L-G-G-G-A-K-Q-A-G-D-V in fibrinogen gamma chain. Following activation integrin alpha-IIb/beta-3 brings about platelet/platelet interaction through binding of soluble fibrinogen. This step leads to rapid platelet aggregation which physically plugs ruptured endothelial surface. In case of HIV-1 infection, the interaction with extracellular viral Tat protein seems to enhance angiogenesis in Kaposi's sarcoma lesions.
Publication Abstract from PubMed
Many questions about the significance of structural features of integrin alpha(V)beta(3) with respect to its mechanism of activation remain. We have determined and re-refined crystal structures of the alpha(V)beta(3) ectodomain linked to C-terminal coiled coils (alpha(V)beta(3)-AB) and four transmembrane (TM) residues in each subunit (alpha(V)beta(3)-1TM), respectively. The alpha(V) and beta(3) subunits with four and eight extracellular domains, respectively, are bent at knees between the integrin headpiece and lower legs, and the headpiece has the closed, low-affinity conformation. The structures differ in the occupancy of three metal-binding sites in the betaI domain. Occupancy appears to be related to the pH of crystallization, rather than to the physiologic regulation of ligand binding at the central, metal ion-dependent adhesion site. No electron density was observed for TM residues and much of the alpha(V) linker. alpha(V)beta(3)-AB and alpha(V)beta(3)-1TM demonstrate flexibility in the linker between their extracellular and TM domains, rather than the previously proposed rigid linkage. A previously postulated interface between the alpha(V) and beta(3) subunits at their knees was also not supported, because it lacks high-quality density, required rebuilding in alpha(V)beta(3)-1TM, and differed markedly between alpha(V)beta(3)-1TM and alpha(V)beta(3)-AB. Together with the variation in domain-domain orientation within their bent ectodomains between alpha(V)beta(3)-AB and alpha(V)beta(3)-1TM, these findings are compatible with the requirement for large structural changes, such as extension at the knees and headpiece opening, in conveying activation signals between the extracellular ligand-binding site and the cytoplasm.
alpha(V)beta(3) Integrin Crystal Structures and Their Functional Implications.,Dong X, Mi LZ, Zhu J, Wang W, Hu P, Luo BH, Springer TA Biochemistry. 2012 Nov 6;51(44):8814-28. doi: 10.1021/bi300734n. Epub 2012 Oct, 29. PMID:23106217[18]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Loftus JC, O'Toole TE, Plow EF, Glass A, Frelinger AL 3rd, Ginsberg MH. A beta 3 integrin mutation abolishes ligand binding and alters divalent cation-dependent conformation. Science. 1990 Aug 24;249(4971):915-8. PMID:2392682
- ↑ Bajt ML, Ginsberg MH, Frelinger AL 3rd, Berndt MC, Loftus JC. A spontaneous mutation of integrin alpha IIb beta 3 (platelet glycoprotein IIb-IIIa) helps define a ligand binding site. J Biol Chem. 1992 Feb 25;267(6):3789-94. PMID:1371279
- ↑ Lanza F, Stierle A, Fournier D, Morales M, Andre G, Nurden AT, Cazenave JP. A new variant of Glanzmann's thrombasthenia (Strasbourg I). Platelets with functionally defective glycoprotein IIb-IIIa complexes and a glycoprotein IIIa 214Arg----214Trp mutation. J Clin Invest. 1992 Jun;89(6):1995-2004. PMID:1602006 doi:http://dx.doi.org/10.1172/JCI115808
- ↑ Chen YP, Djaffar I, Pidard D, Steiner B, Cieutat AM, Caen JP, Rosa JP. Ser-752-->Pro mutation in the cytoplasmic domain of integrin beta 3 subunit and defective activation of platelet integrin alpha IIb beta 3 (glycoprotein IIb-IIIa) in a variant of Glanzmann thrombasthenia. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10169-73. PMID:1438206
- ↑ Grimaldi CM, Chen F, Scudder LE, Coller BS, French DL. A Cys374Tyr homozygous mutation of platelet glycoprotein IIIa (beta 3) in a Chinese patient with Glanzmann's thrombasthenia. Blood. 1996 Sep 1;88(5):1666-75. PMID:8781422
- ↑ Basani RB, Brown DL, Vilaire G, Bennett JS, Poncz M. A Leu117-->Trp mutation within the RGD-peptide cross-linking region of beta3 results in Glanzmann thrombasthenia by preventing alphaIIb beta3 export to the platelet surface. Blood. 1997 Oct 15;90(8):3082-8. PMID:9376589
- ↑ French DL, Coller BS. Hematologically important mutations: Glanzmann thrombasthenia. Blood Cells Mol Dis. 1997;23(1):39-51. PMID:9215749 doi:10.1006/bcmd.1997.0117
- ↑ Ambo H, Kamata T, Handa M, Taki M, Kuwajima M, Kawai Y, Oda A, Murata M, Takada Y, Watanabe K, Ikeda Y. Three novel integrin beta3 subunit missense mutations (H280P, C560F, and G579S) in thrombasthenia, including one (H280P) prevalent in Japanese patients. Biochem Biophys Res Commun. 1998 Oct 29;251(3):763-8. PMID:9790984 doi:10.1006/bbrc.1998.9526
- ↑ Jackson DE, White MM, Jennings LK, Newman PJ. A Ser162-->Leu mutation within glycoprotein (GP) IIIa (integrin beta3) results in an unstable alphaIIbbeta3 complex that retains partial function in a novel form of type II Glanzmann thrombasthenia. Thromb Haemost. 1998 Jul;80(1):42-8. PMID:9684783
- ↑ Ruan J, Schmugge M, Clemetson KJ, Cazes E, Combrie R, Bourre F, Nurden AT. Homozygous Cys542-->Arg substitution in GPIIIa in a Swiss patient with type I Glanzmann's thrombasthenia. Br J Haematol. 1999 May;105(2):523-31. PMID:10233432
- ↑ Ruiz C, Liu CY, Sun QH, Sigaud-Fiks M, Fressinaud E, Muller JY, Nurden P, Nurden AT, Newman PJ, Valentin N. A point mutation in the cysteine-rich domain of glycoprotein (GP) IIIa results in the expression of a GPIIb-IIIa (alphaIIbbeta3) integrin receptor locked in a high-affinity state and a Glanzmann thrombasthenia-like phenotype. Blood. 2001 Oct 15;98(8):2432-41. PMID:11588040
- ↑ Nurden AT, Ruan J, Pasquet JM, Gauthier B, Combrie R, Kunicki T, Nurden P. A novel 196Leu to Pro substitution in the beta3 subunit of the alphaIIbbeta3 integrin in a patient with a variant form of Glanzmann thrombasthenia. Platelets. 2002 Mar;13(2):101-11. PMID:11897046 doi:10.1080/09537100220122466
- ↑ D'Andrea G, Colaizzo D, Vecchione G, Grandone E, Di Minno G, Margaglione M. Glanzmann's thrombasthenia: identification of 19 new mutations in 30 patients. Thromb Haemost. 2002 Jun;87(6):1034-42. PMID:12083483
- ↑ Nair S, Li J, Mitchell WB, Mohanty D, Coller BS, French DL. Two new beta3 integrin mutations in Indian patients with Glanzmann thrombasthenia: localization of mutations affecting cysteine residues in integrin beta3. Thromb Haemost. 2002 Sep;88(3):503-9. PMID:12353082 doi:10.1267/THRO88030503
- ↑ Gonzalez-Manchon C, Butta N, Larrucea S, Arias-Salgado EG, Alonso S, Lopez A, Parrilla R. A variant thrombasthenic phenotype associated with compound heterozygosity of integrin beta3-subunit: (Met124Val)beta3 alters the subunit dimerization rendering a decreased number of constitutive active alphaIIbbeta3 receptors. Thromb Haemost. 2004 Dec;92(6):1377-86. PMID:15583747 doi:04121377
- ↑ Tanaka S, Hayashi T, Yoshimura K, Nakayama M, Fujita T, Amano T, Tani Y. Double heterozygosity for a novel missense mutation of Ile304 to Asn in addition to the missense mutation His280 to Pro in the integrin beta3 gene as a cause of the absence of platelet alphaIIbbeta3 in Glanzmann's thrombasthenia. J Thromb Haemost. 2005 Jan;3(1):68-73. PMID:15634267 doi:JTH990
- ↑ Nair S, Ghosh K, Shetty S, Mohanty D. Mutations in GPIIIa molecule as a cause for Glanzmann thrombasthenia in Indian patients. J Thromb Haemost. 2005 Mar;3(3):482-8. PMID:15748237 doi:JTH1159
- ↑ Dong X, Mi LZ, Zhu J, Wang W, Hu P, Luo BH, Springer TA. alpha(V)beta(3) Integrin Crystal Structures and Their Functional Implications. Biochemistry. 2012 Nov 6;51(44):8814-28. doi: 10.1021/bi300734n. Epub 2012 Oct, 29. PMID:23106217 doi:http://dx.doi.org/10.1021/bi300734n
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