The function of the integrin family of receptors as central mediators of cell-extracellular matrix (ECM) and cell–cell adhesion requires a remarkable convergence of interactions and influences. Integrins must be anchored to the cytoskeleton and bound to extracellular ligands in order to provide firm adhesion, with force transmission across this linkage conferring tissue integrity. Integrin affinity to ligands is highly regulated by cell signaling pathways, altering affinity constants by 1000-fold or more, via a series of long-range conformational transitions. In this review, we first summarize basic, well-known features of integrin conformational states and then focus on new information concerning the impact of mechanical forces on these states and interstate transitions. We also discuss how these effects may impact mechansensitive cell functions and identify unanswered questions for future studies.

The conformational activation of α _IIb β ₃ integrin is crucial for platelet aggregation, a central event in hemostasis and thrombosis. Although activation can be triggered by extracellular arginine-glycine-aspartic acid (RGD)-containing ligands as well as mechanical forces, how these biochemical and mechanical cues exactly govern the structural dynamics of α _IIb β ₃ remains unclear. Here, using all-atom molecular dynamics simulations, we show that mechanical force and RGD binding promote activation α _IIb β ₃ through distinct mechanisms. Mechanical force applied to the RGD-binding site induces long-range, correlated motions of distant parts of the receptor, facilitating head–leg separation. In contrast, RGD binding increases localized, non-correlated fluctuations that weaken leg coordination but do not generate long-range motions. Despite these differences, both cues stabilize the open, extended conformation of α _IIb β ₃ . Together, these findings suggest that mechanical and biochemical stimuli play complementary yet distinct roles in integrin conformational activation. A balance between global coordination and local fluctuations likely governs integrin activation in complex environments where the dominance of mechanical or biochemical cues could lead to distinct activation pathways and functional outcomes.