6BXJ

Structure of a single-chain beta3 integrin

Summary for 6BXJ

• Entry DOI: 10.2210/pdb6bxj/pdb
• Descriptor: Chimera protein of Integrin beta-3 and Integrin alpha-L, MAGNESIUM ION, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: integrin, cell adhesion
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 70447.81

Authors

Thinn, A.M.M.,Wang, Z.,Zhou, D.,Zhao, Y.,Curtis, B.R.,Zhu, J. (deposition date: 2017-12-18, release date: 2018-10-03, Last modification date: 2024-10-09)

Primary citation

Thinn, A.M.M.,Wang, Z.,Zhou, D.,Zhao, Y.,Curtis, B.R.,Zhu, J.
Autonomous conformational regulation of beta3integrin and the conformation-dependent property of HPA-1a alloantibodies.
Proc. Natl. Acad. Sci. U.S.A., 115:E9105-E9114, 2018

PubMed 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 integrins, including αβ and αβ, are the prototypes for understanding integrin structural regulation. The Leu33Pro polymorphism located at the β 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 αβ from αβ and affect their functions with unknown mechanisms. Here we designed a single-chain β subunit that mimics a separation of α/β heterodimer on inside-out activation. Our crystallographic and functional studies show that the single-chain β integrin folds into a bent conformation in solution but spontaneously extends on the cell surface. This demonstrates that the β subunit autonomously drives the membrane-dependent conformational rearrangement during integrin activation. Using the single-chain β integrin, we identified the conformation-dependent property of anti-HPA-1a alloantibodies, which enables them to differently recognize the β in the bent state vs. the extended state and in the complex with α vs. α This study provides deeper understandings of integrin conformational activation on the cell surface.

PubMed: 30209215
DOI: 10.1073/pnas.1806205115

Experimental method

X-RAY DIFFRACTION (2.092 Å)