期刊
ACS CENTRAL SCIENCE
卷 4, 期 5, 页码 548-558出版社
AMER CHEMICAL SOC
DOI: 10.1021/acscentsci.7b00582
关键词
-
资金
- Academy of Finland [303771, 266092]
- Center of Excellence Project [307415]
- European Research Council (Advanced Grant GROWDED-PRO-LIPIDS) [290974]
- Sigrid Juselius Foundation
- Magnus Ehrnrooth Foundation
- Ruth and Nils-Erik Stenback Foundation
- Liv och Halsa Foundation
- University of Helsinki
- ILS doctoral programme at the University of Helsinki
- Czech Science Foundation [208/12/G016]
Membrane proteins are functionally regulated by the composition of the surrounding lipid bilayer. The late endosomal compartment is a central site for the generation of ceramide, a bioactive sphingolipid, which regulates responses to cell stress. The molecular interactions between ceramide and late endosomal transmembrane proteins are unknown. Here, we uncover in atomistic detail the ceramide interaction of Lysosome Associated Protein Transmembrane 4B (LAPTM4B), implicated in ceramide-dependent cell death and autophagy, and its functional relevance in lysosomal nutrient signaling. The ceramide-mediated regulation of LAPTM4B depends on a sphingolipid interaction motif and an adjacent aspartate residue in the protein's third transmembrane (TM3) helix. The interaction motif provides the preferred contact points for ceramide while the neighboring membrane-embedded acidic residue confers flexibility that is subject to ceramide-induced conformational changes, reducing TM3 bending. This facilitates the interaction between LAPTM4B and the amino acid transporter heavy chain 4F2hc, thereby controlling mTORC signaling. These findings provide mechanistic insights into how transmembrane proteins sense and respond to ceramide.
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