1. Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA
2. Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA
3. These authors contributed equally to this work

Correspondence to: Rhoderick E. Brown²Dinshaw J. Patel¹ Email: reb@umn.edu
Email: pateld@mskcc.org
Coordinates have been deposited in the Protein Data Bank under accession codes 1SWX for apo-GLTP and 1SX6 for lactosylceramide-bound GLTP.

Abstract

Lipid transfer proteins are important in membrane vesicle biogenesis and trafficking, signal transduction and immunological presentation processes^{1, 2, 3}. The conserved and ubiquitous mammalian glycolipid transfer proteins (GLTPs) serve as potential regulators of cell processes mediated by glycosphingolipids, ranging from differentiation and proliferation to invasive adhesion, neurodegeneration and apoptosis^{4, 5}. Here we report crystal structures of apo-GLTP (1.65 Å resolution) and lactosylceramide-bound (1.95 Å) GLTP, in which the bound glycosphingolipid is sandwiched, after adaptive recognition, within a previously unknown two-layer all--helical topology. Glycosphingolipid binding specificity is achieved through recognition and anchoring of the sugar-amide headgroup to the GLTP recognition centre by hydrogen bond networks and hydrophobic contacts, and encapsulation of both lipid chains, in a precisely oriented manner within a 'moulded-to-fit' hydrophobic tunnel. A cleft-like conformational gating mechanism, involving two interhelical loops and one -helix of GLTP, could enable the glycolipid chains to enter and leave the tunnel in the membrane-associated state. Mutation and functional analyses of residues in the glycolipid recognition centre and within the hydrophobic tunnel support a framework for understanding how GLTPs acquire and release glycosphingolipids during lipid intermembrane transfer and presentation processes.

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