2k9j

Structural highlights

Disease

ITA2B_HUMAN Defects in ITGA2B 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] [18] [19]}

Function

ITA2B_HUMAN Integrin alpha-IIb/beta-3 is a receptor for fibronectin, fibrinogen, plasminogen, prothrombin, thrombospondin and vitronectin. It recognizes the sequence R-G-D in a wide array of ligands. It 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 cell surface.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

• Integrin 3D structures

References

1. ↑ Poncz M, Rifat S, Coller BS, Newman PJ, Shattil SJ, Parrella T, Fortina P, Bennett JS. Glanzmann thrombasthenia secondary to a Gly273-->Asp mutation adjacent to the first calcium-binding domain of platelet glycoprotein IIb. J Clin Invest. 1994 Jan;93(1):172-9. PMID:8282784 doi:http://dx.doi.org/10.1172/JCI116942
2. ↑ Wilcox DA, Wautier JL, Pidard D, Newman PJ. A single amino acid substitution flanking the fourth calcium binding domain of alpha IIb prevents maturation of the alpha IIb beta 3 integrin complex. J Biol Chem. 1994 Feb 11;269(6):4450-7. PMID:7508443
3. ↑ Wilcox DA, Paddock CM, Lyman S, Gill JC, Newman PJ. Glanzmann thrombasthenia resulting from a single amino acid substitution between the second and third calcium-binding domains of GPIIb. Role of the GPIIb amino terminus in integrin subunit association. J Clin Invest. 1995 Apr;95(4):1553-60. PMID:7706461 doi:http://dx.doi.org/10.1172/JCI117828
4. ↑ Basani RB, Vilaire G, Shattil SJ, Kolodziej MA, Bennett JS, Poncz M. Glanzmann thrombasthenia due to a two amino acid deletion in the fourth calcium-binding domain of alpha IIb: demonstration of the importance of calcium-binding domains in the conformation of alpha IIb beta 3. Blood. 1996 Jul 1;88(1):167-73. PMID:8704171
5. ↑ 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
6. ↑ Grimaldi CM, Chen F, Wu C, Weiss HJ, Coller BS, French DL. Glycoprotein IIb Leu214Pro mutation produces glanzmann thrombasthenia with both quantitative and qualitative abnormalities in GPIIb/IIIa. Blood. 1998 Mar 1;91(5):1562-71. PMID:9473221
7. ↑ Tadokoro S, Tomiyama Y, Honda S, Arai M, Yamamoto N, Shiraga M, Kosugi S, Kanakura Y, Kurata Y, Matsuzawa Y. A Gln747-->Pro substitution in the IIb subunit is responsible for a moderate IIbbeta3 deficiency in Glanzmann thrombasthenia. Blood. 1998 Oct 15;92(8):2750-8. PMID:9763559
8. ↑ Ambo H, Kamata T, Handa M, Kawai Y, Oda A, Murata M, Takada Y, Ikeda Y. Novel point mutations in the alphaIIb subunit (Phe289-->Ser, Glu324-->Lys and Gln747-->Pro) causing thrombasthenic phenotypes in four Japanese patients. Br J Haematol. 1998 Aug;102(3):829-40. PMID:9722314
9. ↑ Ruan J, Peyruchaud O, Alberio L, Valles G, Clemetson K, Bourre F, Nurden AT. Double heterozygosity of the GPIIb gene in a Swiss patient with Glanzmann's thrombasthenia. Br J Haematol. 1998 Sep;102(4):918-25. PMID:9734640
10. ↑ Gonzalez-Manchon C, Fernandez-Pinel M, Arias-Salgado EG, Ferrer M, Alvarez MV, Garcia-Munoz S, Ayuso MS, Parrilla R. Molecular genetic analysis of a compound heterozygote for the glycoprotein (GP) IIb gene associated with Glanzmann's thrombasthenia: disruption of the 674-687 disulfide bridge in GPIIb prevents surface exposure of GPIIb-IIIa complexes. Blood. 1999 Feb 1;93(3):866-75. PMID:9920835
11. ↑ Basani RB, French DL, Vilaire G, Brown DL, Chen F, Coller BS, Derrick JM, Gartner TK, Bennett JS, Poncz M. A naturally occurring mutation near the amino terminus of alphaIIb defines a new region involved in ligand binding to alphaIIbbeta3. Blood. 2000 Jan 1;95(1):180-8. PMID:10607701
12. ↑ Vinciguerra C, Bordet JC, Beaune G, Grenier C, Dechavanne M, Negrier C. Description of 10 new mutations in platelet glycoprotein IIb (alphaIIb) and glycoprotein IIIa (beta3) genes. Platelets. 2001 Dec;12(8):486-95. PMID:11798398 doi:10.1080/095371001317126383
13. ↑ Tanaka S, Hayashi T, Hori Y, Terada C, Han KS, Ahn HS, Bourre F, Tani Y. A Leu55 to Pro substitution in the integrin alphaIIb is responsible for a case of Glanzmann's thrombasthenia. Br J Haematol. 2002 Sep;118(3):833-5. PMID:12181054
14. ↑ 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
15. ↑ Mitchell WB, Li JH, Singh F, Michelson AD, Bussel J, Coller BS, French DL. Two novel mutations in the alpha IIb calcium-binding domains identify hydrophobic regions essential for alpha IIbbeta 3 biogenesis. Blood. 2003 Mar 15;101(6):2268-76. Epub 2002 Nov 7. PMID:12424194 doi:10.1182/blood-2002-07-2266
16. ↑ Kiyoi T, Tomiyama Y, Honda S, Tadokoro S, Arai M, Kashiwagi H, Kosugi S, Kato H, Kurata Y, Matsuzawa Y. A naturally occurring Tyr143His alpha IIb mutation abolishes alpha IIb beta 3 function for soluble ligands but retains its ability for mediating cell adhesion and clot retraction: comparison with other mutations causing ligand-binding defects. Blood. 2003 May 1;101(9):3485-91. Epub 2002 Dec 27. PMID:12506038 doi:10.1182/blood-2002-07-2144
17. ↑ Nurden AT, Breillat C, Jacquelin B, Combrie R, Freedman J, Blanchette VS, Schmugge M, Rand ML. Triple heterozygosity in the integrin alphaIIb subunit in a patient with Glanzmann's thrombasthenia. J Thromb Haemost. 2004 May;2(5):813-9. PMID:15099289 doi:10.1046/j.1538-7836.2004.00711.x
18. ↑ Rosenberg N, Landau M, Luboshitz J, Rechavi G, Seligsohn U. A novel Phe171Cys mutation in integrin alpha causes Glanzmann thrombasthenia by abrogating alphabeta complex formation. J Thromb Haemost. 2004 Jul;2(7):1167-75. PMID:15219201 doi:10.1111/j.1538-7836.2004.00758.x
19. ↑ Jayo A, Pabon D, Lastres P, Jimenez-Yuste V, Gonzalez-Manchon C. Type II Glanzmann thrombasthenia in a compound heterozygote for the alpha IIb gene. A novel missense mutation in exon 27. Haematologica. 2006 Oct;91(10):1352-9. PMID:17018384
20. ↑ Lau TL, Kim C, Ginsberg MH, Ulmer TS. The structure of the integrin alphaIIbbeta3 transmembrane complex explains integrin transmembrane signalling. EMBO J. 2009 May 6;28(9):1351-61. Epub 2009 Mar 12. PMID:19279667 doi:10.1038/emboj.2009.63