| Structural highlights
6bxf is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | CA, GOL, MG, NAG |
| Related: | 6bxb, 6bxj, 6ckb |
| Gene: | ITGB3, GP3A (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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
[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
Cells utilize the adhesion receptor integrins to communicate with their surroundings. Integrin activation and cellular signaling are coupled with the changes from a bent to an extended conformation. The beta3 integrins, including alphaIIbbeta3 that is essential for the function of platelets in hemostasis and thrombosis, and alphaVbeta3 that plays multiple roles in diverse cell types, have been prototypes in understanding integrin structure and function. Despite extensive structural studies, a high-resolution integrin structure in an extended conformation remains to be determined. The human beta3 Leu33Pro polymorphism, located at the PSI domain, defines the human platelet-specific alloantigen HPA-1a/b, to which immune response is a cause of post-transfusion purpura and fetal/neonatal alloimmune thrombocytopenia. The Leu33Pro substitution was also suggested to be a risk factor for thrombosis. Here we report the crystal structure of beta3 headpiece in either Leu33 or Pro33 form, both of which reveal an intermediate and a fully extended conformation coexisting in one crystal. These were used to build the high-resolution structures of full-length beta3 integrin in the intermediate and fully extended states, agreeing well with the corresponding conformations observed by electron microscopy. Our structures reveal how beta3 integrin becomes extended at its beta-knee region and how the flexibility of beta leg domains is determined. In addition, our structures reveal conformational changes of the PSI and I-EGF1 domains upon beta3 extension, which may affect the binding of conformation-dependent anti-HPA-1a alloantibodies. Our structural and functional data show that the Leu33Pro substitution doesn't directly alter the conformation and ligand binding of beta3 integrin.
Structure of an extended beta3 integrin.,Zhou D, Thinn AMM, Zhao Y, Wang Z, Zhu J Blood. 2018 Jul 17. pii: blood-2018-01-829572. doi: 10.1182/blood-2018-01-829572. PMID:30018079[18]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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:https://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
- ↑ Zhou D, Thinn AMM, Zhao Y, Wang Z, Zhu J. Structure of an extended beta3 integrin. Blood. 2018 Jul 17. pii: blood-2018-01-829572. doi: 10.1182/blood-2018-01-829572. PMID:30018079 doi:https://dx.doi.org/10.1182/blood-2018-01-829572
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