Conformational response of α_IIbβ₃ and α_Vβ₃ integrins to force

As major adhesion receptors, integrins transmit biochemical and mechanical signals across the plasma membrane. These functions are regulated by transitions between bent and extended conformations and modulated by force. To understand how force on integrins mediates cellular mechanosensing, we compared two highly homologous integrins, α_IIbβ₃ and α_Vβ₃. These integrins, expressed in circulating platelets vs. solid tissues, respectively, share the β₃ subunit, bind similar ligands and have similar bent and extended conformations. Here, we report that in cells expressing equivalent levels of each integrin, α_IIbβ₃ mediates spreading on softer substrates than α_Vβ₃. These effects correlate with differences in structural dynamics of the two integrins under force. All-atom simulations show that α_IIbβ₃ is more flexible than α_Vβ₃ due to correlated residue motions within the α subunit domains. Single molecule measurements confirm that α_IIbβ₃ extends faster than α_Vβ₃. These results reveal a fundamental relationship between protein function and structural dynamics in cell mechanosensing.