Lipid- packing defects are sufficient to modulate membrane insertion and the bound state of α- synuclein

• 成果类型: Article
• 署名作者: Turke, Miah J.; Raghavan, Krishna M.; Maltseva, Sofiya; Kerr, Daniel H. S.; Adams, Erin J.; Lee, Ka Yee C.
• 署名单位: University of Chicago; University of Chicago; University of Chicago
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2419823122
• 发表日期: 2025-12-22
• 页码: e2419823122
• 关键词: alpha- Synuclein; lipid-packing defects; tryptophan fluorescence; lipid-protein interactions; protein-lipid interactions; secondary structure; binding; vesicles; helix; DYNAMICS; affinity; depends

摘要

alpha- Synuclein is an intrinsically disordered neuronal protein that forms an amphipathic helix when it peripherally binds to lipid membranes. This membrane interaction is integral to the protein's function but is also associated with its dysfunction. Numerous membrane parameters have been identified to promote alpha- synuclein binding such as high negative charge and low lipid-packing density, which corresponds to greater lipid-packing defects- increased spacing between lipids conferred through curvature, unsaturation, or small head-groups. Despite alpha- synuclein's established preference for negatively charged membranes with packing defects, the specific effects that each parameter has on this interaction remains underexplored. With increasing links between alpha- synucleinassociated diseases and changes in lipid composition, it has become more important to delineate how changes in membrane parameters affect alpha- synuclein membrane-interactions. Here, we demonstrate using tryptophan fluorescence spectroscopy that while net negative charge does increase the density of alpha- synuclein bound to a membrane, lipid-packing defects alone are sufficient for alpha- synuclein to insert. Not only do our results establish a lipid-packing defect requirement for alpha- synuclein, but they also reveal a packing defect-dependent shift in the ensemble of binding modes of the protein favoring the insertion of the end of its binding domain-a binding mode which has previously been linked to disease mutants of the protein. Overall, this work establishes the significance of lipid-packing defects in contrast to net negative charge for alpha- synuclein-membrane binding and proposes a lipid-compositionally dependent shift in alpha- synuclein's ensemble of bound conformations, which may be relevant for the protein's function and dysfunction.