Structural basis of lipid transfer by a bridge-like lipid-transfer protein

Yunsik Kang, Katherine S. Lehmann, Hannah Long, Amanda Jefferson, Maria Purice, Marc Freeman and Sarah Clark ()
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Yunsik Kang: Oregon Health & Science University
Katherine S. Lehmann: Oregon Health & Science University
Hannah Long: Oregon State University
Amanda Jefferson: Oregon Health & Science University
Maria Purice: Oregon State University
Marc Freeman: Oregon Health & Science University
Sarah Clark: Oregon State University

Nature, 2025, vol. 642, issue 8066, 242-249

Abstract: Abstract Bridge-like lipid-transport proteins (BLTPs) are an evolutionarily conserved family of proteins that localize to membrane-contact sites and are thought to mediate the bulk transfer of lipids from a donor membrane, typically the endoplasmic reticulum, to an acceptor membrane, such as that of the cell or an organelle1. Although BLTPs are fundamentally important for a wide array of cellular functions, their architecture, composition and lipid-transfer mechanisms remain poorly characterized. Here we present the subunit composition and the cryogenic electron microscopy structure of the native LPD-3 BLTP complex isolated from transgenic Caenorhabditis elegans. LPD-3 folds into an elongated, rod-shaped tunnel of which the interior is filled with ordered lipid molecules that are coordinated by a track of ionizable residues that line one side of the tunnel. LPD-3 forms a complex with two previously uncharacterized proteins, one of which we have named Spigot and the other of which remains unnamed. Spigot interacts with the N-terminal end of LPD-3 where lipids are expected to enter the tunnel, and experiments in multiple model systems indicate that Spigot has a conserved role in BLTP function. Our LPD-3 complex structural data reveal protein–lipid interactions that suggest a model for how the native LPD-3 complex mediates bulk lipid transport and provides a foundation for mechanistic studies of BLTPs.

Date: 2025
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DOI: 10.1038/s41586-025-08918-y

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