Amphipathic Motifs Regulate N-BAR Protein Endophilin B1 Auto-inhibition and Drive Membrane Remodeling

• Published in: Structure (London) 2021-01, Vol.29 (1), p.61-69.e3
• Main Authors: Bhatt, Veer S., Ashley, Robert, Sundborger-Lunna, Anna
• Format: Article
• Language: English
• Subjects: amphipathic helices; auto-inhibition; BAR proteins; membrane remodeling
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2020.09.012

Membrane remodeling is a common theme in a variety of cellular processes. Here, we investigated membrane remodeling N-BAR protein endophilin B1, a critical player in diverse intracellular trafficking events, including mitochondrial and Golgi fission, and apoptosis. We find that endophilin B1 assembles into helical scaffolds on membranes, and that both membrane binding and assembly are driven by interactions between N-terminal helix H0 and the lipid bilayer. Furthermore, we find that endophilin B1 membrane remodeling is auto-inhibited and identify direct SH3 domain-H0 interactions as the underlying mechanism. Our results indicate that lipid composition plays a role in dictating endophilin B1 activity. Taken together, this study provides insight into a poorly understood N-BAR protein family member and highlights molecular mechanisms that may be general for the regulation of membrane remodeling. Our work suggests that interplay between membrane lipids and membrane interacting proteins facilitates spatial and temporal coordination of membrane remodeling. [Display omitted] •Cryo-EM reveals the organization of endophilin B1 dimers assembled on membranes•Endophilin B1 amphipathic motif H0, but not H1i, is critical for membrane binding•Endophilin B1 membrane remodeling activity is auto-inhibited•Endophilin B1 auto-inhibition is mediated by SH3-H0 interactions Bhatt et al. use cryo-EM to reveal the organization of N-BAR protein endophilin B1 assembled on tubulated membranes. Interactions between N-terminal amphipathic motif H0 and membrane lipids direct helical assembly of dimers. Membrane binding and subsequent remodeling is auto-inhibited, mediated by H0-SH3 domain interactions, and influenced by membrane lipid composition.