Enhanced selectivity for sulfatide by engineered human glycolipid transfer protein |
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Authors: | Samygina Valeria R Popov Alexander N Cabo-Bilbao Aintzane Ochoa-Lizarralde Borja Goni-de-Cerio Felipe Zhai Xiuhong Molotkovsky Julian G Patel Dinshaw J Brown Rhoderick E Malinina Lucy |
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Affiliation: | Structural Biology Unit, CIC bioGUNE, Technology Park of Bizkaia, 48160 Derio-Bilbao, Spain. |
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Abstract: | Human glycolipid transfer protein (GLTP) fold represents a novel structural motif for lipid binding/transfer and reversible membrane translocation. GLTPs transfer glycosphingolipids (GSLs) that are key regulators of cell growth, division, surface adhesion, and neurodevelopment. Herein, we report structure-guided engineering of the lipid binding features of GLTP. New crystal structures of wild-type GLTP and two mutants (D48V and A47D‖D48V), each containing bound N-nervonoyl-sulfatide, reveal the molecular basis for selective anchoring of sulfatide (3-O-sulfo-galactosylceramide) by D48V-GLTP. Directed point mutations of "portal entrance" residues, A47 and D48, reversibly regulate sphingosine access to the hydrophobic pocket via a mechanism that could involve homodimerization. "Door-opening" conformational changes by phenylalanines within the hydrophobic pocket are revealed during lipid encapsulation by new crystal structures of bona fide apo-GLTP and GLTP complexed with N-oleoyl-glucosylceramide. The development of "engineered GLTPs" with enhanced specificity for select GSLs provides a potential new therapeutic approach for targeting GSL-mediated pathologies. |
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