A novel superfamily of bridge-like lipid transfer proteins

Lipid transfer proteins mediate nonvesicular transport of lipids at membrane contact sites to regulate the lipid composition of organelle membranes. Recently, a new type of bridge-like lipid transfer protein has emerged; these proteins contain a long hydrophobic groove and can mediate bulk transport of lipids between organelles. Here, we review recent insights into the structure of these proteins and identify a repeating modular unit that we propose to name the repeating β-groove (RBG) domain. This new structural understanding conceptually unifies all the RBG domain-containing lipid transfer proteins as members of an RBG protein superfamily. We also examine the biological functions of these lipid transporters in normal physiology and disease and speculate on the evolutionary origins of RBG proteins in bacteria. VPS13, ATG2, SHIP164, Csf1, and the Hob proteins comprise a novel superfamily of conserved lipid transfer proteins with long hydrophobic grooves.All these long hydrophobic grooves are built from multiple repeating modules that consist of five β-sheets followed by a loop, for which we propose the name the ‘repeating β-groove’ (RBG) domain.RBG proteins carry out lipid transport at membrane contact sites, with functions in lipid homeostasis and membrane biogenesis. Some of these processes require bulk lipid transfer, which appears to be one of the primary molecular functions of RBG proteins.Eukaryotic RBG proteins likely evolved from structurally related prokaryotic proteins that transfer lipids between the inner and outer membranes in Gram-negative bacteria.