期刊
STRUCTURE
卷 19, 期 11, 页码 1644-1654出版社
CELL PRESS
DOI: 10.1016/j.str.2011.09.011
关键词
-
资金
- Spanish Ministerio de Ciencia e Innovacion (MICINN) [BFU2010-17711]
- Russian Foundation for Basic Research [09-04-00313]
- USPHS [NIGMS GM45928, NCI CA121493]
- Abby Rockefeller Mauze Trust
- Maloris and Hormel Foundations
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 parallel to 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据