Functional unfolding of the integrin αX transmembrane helix.

In biological membranes, proteins face a fundamentally different environment than in water. To avoid untenable lipid contacts with polar backbone atoms, they use the continuous hydrogen bonding achieved by α-helices or β-barrels to traverse membranes. Here, we show that integrin αX, and by homology αM, undermine this paradigm by partially unfolding the N-terminal third of their transmembrane (TM) helix. Unfolding results in a dynamic, frayed helix that weakens the association with its partnering β2 subunit to lower the activation threshold of integrin αXβ2-mediated cell adhesion. The extent of unfolding depends on membrane geometry, thereby establishing a mechanism for sensing membrane properties. The combination of adhesive control with sensory capacity in integrin αXβ2 and αMβ2 may achieve membrane localization-dependent receptor activation in leukocyte phagocytosis. The unfolding of the αX TM helix arises from a high number of α-helix-destabilizing residues that TM helices in general approach but do not exceed. Accordingly, backbone dynamics of TM helices may disrupt hydrogen bonds, modulate protein function, and optimize TM helix rigidity.