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 α-X, and by homology α-M, undermine this paradigm by partially unfolding the N-terminal third of their transmembrane helix. Unfolding results in a dynamic, frayed helix that weakens the association with its partnering β2 subunit to lower the activation threshold of integrin α-Xβ2-mediated cell adhesion. The extent of unfolding depends on membrane geometry, thereby establishing a novel mechanism for sensing membrane properties. The combination of adhesive control with sensory capacity in integrin α-Xβ2 and α-Mβ2 may achieve membrane localization-dependent receptor activation in leukocyte phagocytosis. The unfolding of the α-X transmembrane helix arises from a high number of α-helix-destabilizing residues that transmembrane helices in general approach but do not exceed. Accordingly, backbone dynamics of transmembrane helices may disrupt hydrogen bonds, modulate protein function, and optimize transmembrane helix rigidity.
Tobias S. Ulmer (Sun,) studied this question.