Disordered proteins and bar domains collaborate to remodel membranes.

Abstract

Membrane curvature generation is critical for multiple cellular pathways from endocytosis and autophagy to the biogenesis of most organelles. Scaffolding of the membrane surface by proteins with inherently curved membrane binding interfaces is an established mechanism of membrane remodeling. Among the most commonly studied membrane scaffolds are proteins that contain BAR (bin/amphiphysin/rvs) domains. Assembly of BAR domains into a helical coat has been shown to remodel flat membranes into tubular architectures. However, many BAR domains are found within proteins that also contain domains with significant regions of intrinsic disorder. How might these domains contribute to membrane remodeling? Our previous and ongoing work uses quantitative fluorescence-based assays to demonstrate that crowding among intrinsically disordered domains generates steric pressure that contributes to membrane bending. In particular, when disordered domains are coupled to BAR domains, the scaffolding and crowding mechanisms reinforce one another, driving highly efficient membrane tubulation and fission. Our previous work demonstrated this mechanism for Amphiphysin. Our current work evaluates the concept in a larger group of BAR-domain containing proteins, including endophilin. Collectively, this body of work is demonstrating that BAR domain-containing proteins, when coupled to disordered domains, are potent drivers of membrane fission.