Topological Adaptation of Transmembrane Domains to the Force-Modulated Lipid Bilayer Is a Basis of Sensing Mechanical Force

Cells can sense and respond to various mechanical stimuli from their surrounding environment. One of the explanations for mechanosensitivity, a lipid-bilayer model, suggests that a stretch of the membrane induced by mechanical force alters the physical state of the lipid bilayer, driving mechanosensors to assume conformations better matched to the altered membrane. However, mechanosensors of this class are restricted to ion channels. Here, we reveal that integrin αIIbβ3, a prototypic adhesion receptor, can be activated by various mechanical stimuli including stretch, shear stress, and osmotic pressure. The force-induced integrin activation was not dependent on its known intracellular activation signaling events and was even observed in reconstituted cell-free liposomes. Instead, these mechanical stimuli were found to alter the lipid embedding of the integrin β3 transmembrane domain (TMD) and subsequently weaken the αIIb-β3 TMD interaction, which results in activation of the receptor. Moreover, artificial modulation of the membrane curvature near integrin αIIbβ3 can induce its activation in cells as well as in lipid nanodiscs, suggesting that physical deformation of the lipid bilayer, either by mechanical force or curvature, can induce integrin activation. Thus, our results establish the adhesion receptor as a bona fide mechanosensor that directly senses and responds to the force-modulated lipid environment. Furthermore, this study expands the lipid-bilayer model by suggesting that the force-induced topological change of TMDs and subsequent alteration in the TMD interactome is a molecular basis of sensing mechanical force transmitted via the lipid bilayer. [Display omitted] •Mechanical stretch of the membrane changes the topology of the β3 transmembrane domain•Mechanical force disrupts integrin αIIb-β3 transmembrane domain interaction•Physical deformation of the membrane can directly activate integrin αIIbβ3•Integrin αIIbβ3 is a mechanoreceptor sensing mechanical forces in the lipid bilayer Kim et al. propose an integral membrane protein, integrin αIIbβ3, as a mechanosensor and clarify its force-dependent activity control mechanism. Force-sensitive topological change of transmembrane domains within the lipid bilayer is suggested as a key feature of mechanosensitivity.