title: The liganding of glycolipid transfer protein is controlled by glycolipid acyl structure.
abstract: Glycosphingolipids (GSLs) play major roles in cellular growth and development. Mammalian glycolipid transfer proteins (GLTPs) are potential regulators of cell processes mediated by GSLs and display a unique architecture among lipid binding/transfer proteins. The GLTP fold represents a novel membrane targeting/interaction domain among peripheral proteins. Here we report crystal structures of human GLTP bound to GSLs of diverse acyl chain length, unsaturation, and sugar composition. Structural comparisons show a highly conserved anchoring of galactosyl- and lactosyl-amide headgroups by the GLTP recognition center. By contrast, acyl chain chemical structure and occupancy of the hydrophobic tunnel dictate partitioning between sphingosine-in and newly-observed sphingosine-out ligand-binding modes. The structural insights, combined with computed interaction propensity distributions, suggest a concerted sequence of events mediated by GLTP conformational changes during GSL transfer to and/or from membranes, as well as during GSL presentation and/or transfer to other proteins.
authors.affiliation: Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Lucy
authors.initials: L
authors.lastname: Malinina
authors.forename: Margarita L
authors.initials: ML
authors.lastname: Malakhova
authors.forename: Alex T
authors.initials: AT
authors.lastname: Kanack
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.forename: Rhoderick E
authors.initials: RE
authors.lastname: Brown
authors.forename: Dinshaw J
authors.initials: DJ
authors.lastname: Patel
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D006017:Glycolipids / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D013110:Sphingosine / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D002352:Carrier Proteins; D006017:Glycolipids; D008024:Ligands; C030363:lipid transfer protein; D013110:Sphingosine