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Functional unfolding of the integrin αX transmembrane helix.

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Bibliographic Details
Title: Functional unfolding of the integrin αX transmembrane helix.
Authors: Vu, Han N.1, Lee, Minhyeong2, Situ, Alan J.1, An, Woojin3, Ley, Klaus4, Kim, Chungho2 chungho@korea.ac.kr, Ulmer, Tobias S.1 tulmer@usc.edu
Source: Proceedings of the National Academy of Sciences of the United States of America. 9/23/2025, Vol. 122 Issue 38, p1-9. 9p.
Subjects: Integrins, Cell adhesion, Bilayer lipid membranes, Denaturation of proteins, Physiology, Phagocytosis, Hydrogen bonding
Abstract: 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. [ABSTRACT FROM AUTHOR]
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Database: Engineering Source
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Abstract: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. [ABSTRACT FROM AUTHOR]
ISSN:00278424
DOI:10.1073/pnas.2507966122