Conformational Equilibrium of Human Platelet Integrin Investigated by Three-Dimensional Electron Cryo-Microscopy

Sub-cellular Biochemistry
Dorit Hanein, Niels Volkmann

Abstract

Integrins are bidirectional transmembrane receptors that play central roles in hemostasis and arterial thrombosis. They have been subject to structural studies for many years, in particular using X-ray crystallography, nuclear magnetic resonance spectroscopy, and two-dimensional negative stain electron microscopy. Despite considerable progress, a full consensus on the molecular mechanism of integrin activation is still lacking. Three-dimensional reconstructions of full-length human platelet integrin αIIbβ3 in lipid-bilayer nanodiscs obtained by electron cryo-microscopy and single-particle reconstruction have shed new light on the activation process. These studies show that integrin αIIbβ3 exists in a continuous conformational equilibrium ranging from a compact nodular conformation similar to that obtained in crystal structures to a fully extended state with the leg domains separated. This equilibrium is shifted towards the extended conformation when extracellular ligands, cytosolic activators and lipid-bilayer nanodiscs are added. Addition of cytosolic activators and extracellular ligands in the absense of nanodiscs produces significantly less dramatic shifts, emphasizing the importance of the membrane bilayer in the activation...Continue Reading

Citations

May 4, 2021·Frontiers in Cell and Developmental Biology·Wolfgang M J ObermannJohannes A Eble
Jan 31, 2020·Journal of Medicinal Chemistry·Yajun Zheng, Katerina Leftheris
Sep 11, 2021·Proceedings of the National Academy of Sciences of the United States of America·Simona SorrentinoOhad Medalia

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