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J Cell Sci. 2020 Mar 19. pii: jcs.242404. doi: 10.1242/jcs.242404. [Epub ahead of print]

Induction of ligand promiscuity of αVβ3 integrin by mechanical force.

Author information

1
Zoological Institute, Cell- and Neurobiology, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
2
Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
3
Institute of Functional Interfaces (IFG), Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
4
Faculty of Medicine and Health Technology and BioMediTech, Tampere University, Tampere, Finland and Fimlab Laboratories, Tampere, Finland.
5
DFG-Center for Functional Nanostructures, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
6
WPI Nano Life Science Institute, Kanazawa University, Kanazawa, Japan.
7
Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland bernhard.wehrle-haller@unige.ch martin.bastmeyer@kit.edu.
8
Zoological Institute, Cell- and Neurobiology, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany bernhard.wehrle-haller@unige.ch martin.bastmeyer@kit.edu.

Abstract

αVβ3 integrin can bind to multiple extracellular matrix proteins, including vitronectin (Vn) and fibronectin (Fn), which are often presented to cells in culture as homogenous substrates. However, in tissues, cells experience highly complex and changing environments. To better understand integrin ligand selection in such complex environments, we employed binary-choice substrates of Fn and Vn to dissect αVβ3 integrin-mediated binding to different ligands on the subcellular scale. Super-resolution imaging revealed that αVβ3 integrin preferred binding to Vn under various conditions. In contrast, binding to Fn required higher mechanical load on αVβ3 integrin. Integrin mutations, structural analysis, and chemical inhibition experiments indicated that the degree of hybrid domain swing-out is relevant for the selection between Fn and Vn; only a force-mediated, full hybrid domain swing-out facilitated αVβ3-Fn binding. Thus, force-dependent conformational changes in αVβ3 integrin increased the diversity of available ligands for binding and therefore enhanced the ligand promiscuity of this integrin.

KEYWORDS:

ECM; Fibronectin; Focal adhesions; Ligand selection; Mechanosensing; αVβ3 integrin

PMID:
32193334
DOI:
10.1242/jcs.242404

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