Functional unfolding of the integrin αX transmembrane helix

• 成果类型: Article
• 署名作者: Vu, Han N.; Lee, Minhyeong; Situ, Alan J.; An, Woojin; Ley, Klaus; Kim, Chungho; Ulmer, Tobias S.
• 署名单位: University of Southern California; Korea University; University of Southern California; University System of Georgia; Augusta University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12167
• DOI: 10.1073/pnas.2507966122
• 发表日期: 2025-09-23
• 关键词: protein interactions; chemical-shifts; membrane; reveals; relaxation; STABILITY; backbone; residues; sequence; receptor

摘要

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 alpha- helices or beta- barrels to traverse membranes. Here, we show that integrin alpha X, and by homology alpha M, 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 beta 2 subunit to lower the activation threshold of integrin alpha X beta 2-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 alpha X beta 2 and alpha M beta 2 may achieve membrane localization-dependent receptor activation in leukocyte phagocytosis. The unfolding of the alpha X TM helix arises from a high number of alpha- 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.