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From Proteopedia
Structure of a single-chain beta3 integrin
Structural highlights
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 PubMedIntegrin alpha/beta heterodimer adopts a compact bent conformation in the resting state, and upon activation undergoes a large-scale conformational rearrangement. During the inside-out activation, signals impinging on the cytoplasmic tail of beta subunit induce the alpha/beta separation at the transmembrane and cytoplasmic domains, leading to the extended conformation of the ectodomain with the separated leg and the opening headpiece that is required for the high-affinity ligand binding. It remains enigmatic which integrin subunit drives the bent-to-extended conformational rearrangement in the inside-out activation. The beta3 integrins, including alphaIIbbeta3 and alphaVbeta3, are the prototypes for understanding integrin structural regulation. The Leu33Pro polymorphism located at the beta3 PSI domain defines the human platelet-specific alloantigen (HPA) 1a/b, which provokes the alloimmune response leading to clinically important bleeding disorders. Some, but not all, anti-HPA-1a alloantibodies can distinguish the alphaIIbbeta3 from alphaVbeta3 and affect their functions with unknown mechanisms. Here we designed a single-chain beta3 subunit that mimics a separation of alpha/beta heterodimer on inside-out activation. Our crystallographic and functional studies show that the single-chain beta3 integrin folds into a bent conformation in solution but spontaneously extends on the cell surface. This demonstrates that the beta3 subunit autonomously drives the membrane-dependent conformational rearrangement during integrin activation. Using the single-chain beta3 integrin, we identified the conformation-dependent property of anti-HPA-1a alloantibodies, which enables them to differently recognize the beta3 in the bent state vs. the extended state and in the complex with alphaIIb vs. alphaV This study provides deeper understandings of integrin conformational activation on the cell surface. Autonomous conformational regulation of beta3 integrin and the conformation-dependent property of HPA-1a alloantibodies.,Thinn AMM, Wang Z, Zhou D, Zhao Y, Curtis BR, Zhu J Proc Natl Acad Sci U S A. 2018 Sep 25;115(39):E9105-E9114. doi:, 10.1073/pnas.1806205115. Epub 2018 Sep 12. PMID:30209215[18] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Large Structures | Curtis, B R | Thinn, A M.M | Wang, Z | Zhao, Y | Zhou, D | Zhu, J | Cell adhesion | Integrin
