The liganding of glycolipid transfer protein is controlled by glycolipid acyl structure.
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.
Malinina
Lucy
L
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
Malakhova
Margarita L
ML
Kanack
Alex T
AT
Lu
Min
M
Abagyan
Ruben
R
Brown
Rhoderick E
RE
Patel
Dinshaw J
DJ
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
D002352:Carrier Proteins; D006017:Glycolipids; D008024:Ligands; C030363:lipid transfer protein; D013110:Sphingosine