Autonomous conformational regulation of β3 integrin and the conformation-dependent property of HPA-1a alloantibodies

Aye Myat Myat Thinn, Zhengli Wang, Dongwen Zhou, Yan Zhao, Brian R. Curtis, Jieqing Zhu
2018 Proceedings of the National Academy of Sciences of the United States of America  
Integrin α/β 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 β subunit induce the α/β 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
more » ... emains enigmatic which integrin subunit drives the bent-to-extended conformational rearrangement in the inside-out activation. The β 3 integrins, including α IIb β 3 and α V β 3 , are the prototypes for understanding integrin structural regulation. The Leu33Pro polymorphism located at the β 3 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 α IIb β 3 from α V β 3 and affect their functions with unknown mechanisms. Here we designed a single-chain β 3 subunit that mimics a separation of α/β heterodimer on inside-out activation. Our crystallographic and functional studies show that the single-chain β 3 integrin folds into a bent conformation in solution but spontaneously extends on the cell surface. This demonstrates that the β 3 subunit autonomously drives the membrane-dependent conformational rearrangement during integrin activation. Using the single-chain β 3 integrin, we identified the conformation-dependent property of anti-HPA-1a alloantibodies, which enables them to differently recognize the β 3 in the bent state vs. the extended state and in the complex with α IIb vs. α V . This study provides deeper understandings of integrin conformational activation on the cell surface. integrin structure | integrin activation | conformational change | human platelet alloantigen 1 | alloimmune thrombocytopenia
doi:10.1073/pnas.1806205115 fatcat:l2e5qlio3bhq5jkbozg5wnmcqe