Enhanced selectivity for sulfatide by engineered human glycolipid transfer protein

Valeria R. Samygina, Alexander N. Popov, Aintzane Cabo-Bilbao, Borja Ochoa-Lizarralde, Felipe Goni-De-Cerio, Xiuhong Zhai, Julian G. Molotkovsky, Dinshaw J. Patel, Rhoderick E. Brown, Lucy Malinina

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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 A47DD48V), 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.

Original languageEnglish (US)
Pages (from-to)1644-1654
Number of pages11
Issue number11
StatePublished - Nov 9 2011


Cite this

Samygina, V. R., Popov, A. N., Cabo-Bilbao, A., Ochoa-Lizarralde, B., Goni-De-Cerio, F., Zhai, X., Molotkovsky, J. G., Patel, D. J., Brown, R. E., & Malinina, L. (2011). Enhanced selectivity for sulfatide by engineered human glycolipid transfer protein. Structure, 19(11), 1644-1654. https://doi.org/10.1016/j.str.2011.09.011