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Autonomous conformational regulation of β3 integrin and the conformation-dependent property of HPA-1a alloantibodies.
- Source :
- Proceedings of the National Academy of Sciences of the United States of America; 9/25/2018, Vol. 115 Issue 39, pE9105-E9114, 10p
- Publication Year :
- 2018
-
Abstract
- 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 which integrin subunit drives the bent-to-extended conformational rearrangement in the inside-out activation. The β<subscript>3</subscript> integrins, including α<subscript>IIb</subscript>β<subscript>3</subscript> and α<subscript>V</subscript>β<subscript>3</subscript>, are the prototypes for understanding integrin structural regulation. The Leu33Pro polymorphism located at the β<subscript>3</subscript> 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<subscript>IIb</subscript>β<subscript>3</subscript> from α<subscript>V</subscript>β<subscript>3</subscript> and affect their functions with unknown mechanisms. Here we designed a single-chain β<subscript>3</subscript> subunit that mimics a separation of α/β heterodimer on inside-out activation. Our crystallographic and functional studies show that the single-chain β<subscript>3</subscript> integrin folds into a bent conformation in solution but spontaneously extends on the cell surface. This demonstrates that the β<subscript>3</subscript> subunit autonomously drives the membrane-dependent conformational rearrangement during integrin activation. Using the single-chain β<subscript>3</subscript> integrin, we identified the conformation-dependent property of anti-HPA-1a alloantibodies, which enables them to differently recognize the β<subscript>3</subscript> in the bent state vs. the extended state and in the complex with α<subscript>IIb</subscript> vs. α<subscript>V</subscript>. This study provides deeper understandings of integrin conformational activation on the cell surface. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 115
- Issue :
- 39
- Database :
- Complementary Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 132038125
- Full Text :
- https://doi.org/10.1073/pnas.1806205115