Enhanced selectivity for sulfatide by engineered human glycolipid transfer protein Journal Article
| Authors: | 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. |
| Article Title: | Enhanced selectivity for sulfatide by engineered human glycolipid transfer protein |
| 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 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. © 2011 Elsevier Ltd. All rights reserved. |
| Keywords: | unclassified drug; binding affinity; amino acid substitution; cell protein; protein binding; wild type; protein multimerization; carrier proteins; substrate specificity; crystal structure; hydrogen bonding; models, molecular; crystallography, x-ray; binding sites; conformational transition; protein structure; point mutation; sphingosine; galactosylceramide; glycolipid transfer protein; hydrophobic and hydrophilic interactions; surface properties; protein engineering; 3 o sulfo galactosylceramide; n nervonoylsulfatide; n oleoylglucosylceramide; phenylalanine derivative; sulfatide; sulfoglycosphingolipids |
| Journal Title: | Structure |
| Volume: | 19 |
| Issue: | 11 |
| ISSN: | 0969-2126 |
| Publisher: | Cell Press |
| Date Published: | 2011-11-09 |
| Start Page: | 1644 |
| End Page: | 1654 |
| Language: | English |
| DOI: | 10.1016/j.str.2011.09.011 |
| PROVIDER: | scopus |
| PMCID: | PMC3220887 |
| PUBMED: | 22078563 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 9 December 2011" - "CODEN: STRUE" - "Source: Scopus" |
