The cryo-EM structure of the SNX\u2013BAR Mvp1 tetramer

Marijn G J Ford,Rajesh Ramachandran,Natalia V Varlakhanova,Dapeng Sun,Peijun Zhang,Bryan A Tornabene

doi:10.1038/s41467-020-15110-5

Abstract

Sorting nexins (SNX) are a family of PX domain-containing proteins with pivotal roles in trafficking and signaling. SNX-BARs, which also have a curvature-generating Bin/Amphiphysin/Rvs (BAR) domain, have membrane-remodeling functions, particularly at the endosome. The minimal PX-BAR module is a dimer mediated by BAR-BAR interactions. Many SNX-BAR proteins, however, additionally have low-complexity N-terminal regions of unknown function. Here, we present the cryo-EM structure of the full-length SNX-BAR Mvp1, which is an autoinhibited tetramer. The tetramer is a dimer of dimers, wherein the membrane-interacting BAR surfaces are sequestered and the PX lipid-binding sites are occluded. The N-terminal low-complexity region of Mvp1 is essential for tetramerization. Mvp1 lacking its N-terminus is dimeric and exhibits enhanced membrane association. Membrane binding and remodeling by Mvp1 therefore requires unmasking of the PX and BAR domain lipid-interacting surfaces. This work reveals a tetrameric configuration of a SNX-BAR protein that provides critical insight into SNX-BAR function and regulation.

Highlights

Sorting nexins (SNX) are a family of PX domain-containing proteins with pivotal roles in trafficking and signaling
SNX–BAR proteins are involved in several cellular processes that depend upon membrane remodeling, including protein and lipid trafficking to and from the endosome, endocytosis, and autophagy[5,6,7]
Current models for SNX–BAR-mediated membrane remodeling propose that both the PX and BAR domains have to be engaged with the membrane to ensure specificity and efficient binding

Summary

Introduction

Sorting nexins (SNX) are a family of PX domain-containing proteins with pivotal roles in trafficking and signaling. Membrane binding and remodeling by Mvp[1] requires unmasking of the PX and BAR domain lipid-interacting surfaces. Sorting nexins (SNX) are a large and varied family of phoxhomology (PX) domain-containing proteins with functions in membrane trafficking and remodeling, signaling, and organelle movement[1,2]. SNX–BAR proteins form a subfamily that is characterized by the presence of a membrane-remodeling or curvature-sensing Bin/Amphiphysin/Rvs (BAR) domain[3] in addition to the PX domain which, typically, is a lipid-binding module[4]. While some SNX–BAR proteins consist only of their PX–BAR modules, others, including those involved in retromer-mediated retrograde trafficking and autophagic processes[5,10] have, in addition, a low-complexity Nterminal region, the function of which is unclear. This work reveals a mechanism of regulation of Mvp[1] function by self-assembly

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Results

Conclusion