Seipin forms a flexible cage at lipid droplet formation sites

Henning Arlt,Xuewu Sui,Joel M Goodman,Fred A Hamprecht,Carson Adams,Frank Dimaio,Tobias C Walther,Brayden Folger,Robert V Farese,Roman Remme,Xiao Chen,Maofu Liao

doi:10.1038/s41594-021-00718-y

Abstract

Lipid droplets (LDs) form in the endoplasmic reticulum by phase separation of neutral lipids. This process is facilitated by the seipin protein complex, which consists of a ring of seipin monomers, with a yet unclear function. Here, we report a structure of S. cerevisiae seipin based on cryogenic-electron microscopy and structural modeling data. Seipin forms a decameric, cage-like structure with the lumenal domains forming a stable ring at the cage floor and transmembrane segments forming the cage sides and top. The transmembrane segments interact with adjacent monomers in two distinct, alternating conformations. These conformations result from changes in switch regions, located between the lumenal domains and the transmembrane segments, that are required for seipin function. Our data indicate a model for LD formation in which a closed seipin cage enables triacylglycerol phase separation and subsequently switches to an open conformation to allow LD growth and budding.

Highlights

Lipid droplets (LDs) form in the endoplasmic reticulum by phase separation of neutral lipids
Understanding the function of seipin is crucial to deciphering the mechanism of LD formation from LD assembly protein complexes (LDACs) in the endoplasmic reticulum (ER)
We report a structural model for most of the seipin protein of S. cerevisiae that combines a high confidence 3.2-Å molecular model based on cryogenic-electron microscopy (cryo-EM) of seipin’s lumenal domains, the switch regions and TM segments, with an extended molecular model of the TM segments generated by an AI structure-prediction approach

Summary

Introduction

Lipid droplets (LDs) form in the endoplasmic reticulum by phase separation of neutral lipids. This process is facilitated by the seipin protein complex, which consists of a ring of seipin monomers, with a yet unclear function. Lipid droplets (LDs) are cellular organelles with a primary function of storing lipids for energy generation and membrane biogenesis[1,2]. They serve as hubs of lipid metabolism, platforms for virus assembly and organizing centers of innate immunity[3,4,5]. The lumenal domains form a ring of hydrophobic helices oriented toward the center of the toroid complex and are predicted to insert into the lumenal leaflet of the ER membrane[18,20,21]

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Results

Conclusion