Force-Regulated Spontaneous Conformational Changes of Integrins α₅β₁ and α_Vβ₃

High Resolution Image Download MS PowerPoint Slide Integrins are cell surface nanosized receptors crucial for cell motility and mechanosensing of the extracellular environment, which are often targeted for the development of biomaterials and nanomedicines. As a key feature of integrins, their activity, structure and behavior are highly mechanosensitive, which are regulated by mechanical forces down to pico-Newton scale. Using single-molecule biomechanical approaches, we compared the force-modulated ectodomain bending/unbending conformational changes of two integrin species, α 5 β 1 and α V β 3 . It was found that the conformation of integrin α 5 β 1 is determined by a threshold head-to-tail tension. By comparison, integrin α V β 3 exhibits bistability even without force and can spontaneously transition between the bent and extended conformations with an apparent transition time under a wide range of forces. Molecular dynamics simulations observed almost concurrent disruption of ∼2 hydrogen bonds during integrin α 5 β 1 unbending, but consecutive disruption of ∼7 hydrogen bonds during integrin α V β 3 unbending. Accordingly, we constructed a canonical energy landscape for integrin α 5 β 1 with a single energy well that traps the integrin in the bent state until sufficient force tilts the energy landscape to allow the conformational transition. In contrast, the energy landscape of integrin α V β 3 conformational changes was constructed with hexa-stable intermediate states and intermediate energy barriers that segregate the conformational change process into multiple small steps. Our study elucidates the different biomechanical inner workings of integrins α 5 β 1 and α V β 3 at the submolecular level, helps understand their mechanosignaling processes and how their respective functions are facilitated by their distinctive mechanosensitivities, and provides useful design principles for the engineering of protein-based biomechanical nanomachines.