The liganding of glycolipid transfer protein is controlled by glycolipid acyl structure

Lucy Malinina, Margarita L. Malakhova, Alex T. Kanack, Min Lu, Ruben Abagyan, Rhoderick E. Brown, Dinshaw J. Patel

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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.

Original languageEnglish (US)
Pages (from-to)1996-2011
Number of pages16
JournalPLoS biology
Volume4
Issue number11
DOIs
StatePublished - Nov 1 2006

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Malinina, L., Malakhova, M. L., Kanack, A. T., Lu, M., Abagyan, R., Brown, R. E., & Patel, D. J. (2006). The liganding of glycolipid transfer protein is controlled by glycolipid acyl structure. PLoS biology, 4(11), 1996-2011. https://doi.org/10.1371/journal.pbio.0040362