Seipin forms a flexible cage at lipid droplet formation sites

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 yet unclear function. Here, we report a structure of yeast seipin based on cryo-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 suggest a model for LD formation in which a closed seipin cage enables TG phase separation and subsequently switches to an open conformation to allow LD growth and budding.