| Title: |
Study of Protein-Protein Interactions in Septin Assembly: Multiple amphipathic helix domains cooperate in binding to the lipid membrane. |
| Authors: |
Mofidi, S. Mahsa; Sahoo, Abhilash; Edelmaier, Christopher J.; Klawa, Stephen J.; Freeman, Ronit; Gladfelter, Amy; Forest, M. Gregory; Nazockdast, Ehssan; Hanson, Sonya M. |
| Source: |
PLoS Computational Biology; 4/27/2026, Vol. 22 Issue 4, p1-20, 20p |
| Subject Terms: |
PROTEIN-protein interactions; PROTEIN domains; MEMBRANE proteins; MOLECULAR dynamics; MEMBRANE lipids; BIOLOGICAL membranes; CYTOSKELETAL proteins |
| Abstract: |
Septins are a conserved family of cytoskeletal proteins known for sensing micron-scale membrane curvature via amphipathic helix (AH) domains. While cooperative interactions in septin assembly have been suggested, the molecular mechanisms governing membrane binding and assembly remain unclear. Building on prior findings, we use all-atom molecular dynamics simulations to examine how single and paired extended AH domains, derived from Cdc12, interact with lipid bilayers. We find that a single membrane-bound AH adopts a bent conformation upon membrane association. In solution, a second AH peptide preferentially interacts with the bound peptide through conserved salt bridges, favoring an antiparallel arrangement. Simulations of covalently linked AH tandems confirm the stability of this configuration. When two AH domains are membrane-bound, they induce localized lipid packing defects, reduce tail order, and exhibit slight peptide displacement on planar bilayers. These observations suggest a cooperative AH binding mechanism and are consistent with models in which lipid packing defects facilitate multivalent AH engagement in curved membrane environments. Our findings advance the mechanistic understanding of septin-membrane interactions and highlight the role of cooperative AH domain binding in stabilizing higher-order structures. Author summary: Cells sense and respond to their shape in order to grow, divide, and organize internal structures. Septins are a family of proteins that help cells detect membrane curvature, allowing them to assemble at specific cellular locations. A key component of this process is the amphipathic helix, a short protein segment that is inserted into membranes. While previous studies suggested that these helices may work together, the details of this cooperation were not well understood. Using computer simulations, we explore how helices from yeast septins interact with each other and with lipid membranes. We found that a single helix bends into a curved shape upon binding to the membrane and that a second helix preferentially associates with it in a specific arrangement. When two helices are present, they locally alter membrane structure in ways that can favor curved membrane environments. These results show how small, cooperative interactions can help septins sense and stabilize membrane shape, providing insight into how cells organize their internal architecture. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |