Induction of ligand promiscuity of αVβ3 integrin by mechanical force.
JOURNAL OF CELL SCIENCE(2020)
摘要
alpha V beta 3 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 alpha V beta 3 integrin-mediated binding to different ligands on the subcellular scale. Super-resolution imaging revealed that alpha V beta 3 integrin preferred binding to Vn under various conditions. In contrast, binding to Fn required higher mechanical load on alpha V beta 3 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 alpha V beta 3-Fn binding. Thus, force-dependent conformational changes in alpha V beta 3 integrin increased the diversity of available ligands for binding and therefore enhanced the ligand promiscuity of this integrin. This article has an associated First Person interview with the first author of the paper.
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关键词
alpha V beta 3 integrin,ECM,Ligand selection,Focal adhesions,Fibronectin,Mechanosensing
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