A Ceramide-Regulated Element in the Late Endosomal Protein LAPTM4B Controls Amino Acid Transporter Interaction

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http://hdl.handle.net/10138/242588

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Zhou , K , Dichlberger , A , Martinez-Seara , H , Nyholm , T K M , Li , S , Kim , Y A , Vattulainen , I , Ikonen , E & Blom , T 2018 , ' A Ceramide-Regulated Element in the Late Endosomal Protein LAPTM4B Controls Amino Acid Transporter Interaction ' , ACS central science , vol. 4 , no. 5 , pp. 548-558 . https://doi.org/10.1021/acscentsci.7b00582

Title: A Ceramide-Regulated Element in the Late Endosomal Protein LAPTM4B Controls Amino Acid Transporter Interaction
Author: Zhou, Kecheng; Dichlberger, Andrea; Martinez-Seara, Hector; Nyholm, Thomas K. M.; Li, Shiqian; Kim, Young Ah; Vattulainen, Ilpo; Ikonen, Elina; Blom, Tomas
Contributor organization: Medicum
Department of Anatomy
University of Helsinki
Department of Physics
Lipid Trafficking Lab
Date: 2018-05-23
Language: eng
Number of pages: 11
Belongs to series: ACS central science
ISSN: 2374-7943
DOI: https://doi.org/10.1021/acscentsci.7b00582
URI: http://hdl.handle.net/10138/242588
Abstract: 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.
Subject: MEMBRANE-PROTEINS
TRANSMEMBRANE HELIX
COUPLED RECEPTOR
CANCER-CELLS
DEATH
ACTIVATION
RESISTANCE
AUTOPHAGY
RESIDUES
POSITION
3111 Biomedicine
116 Chemical sciences
Peer reviewed: Yes
Rights: other
Usage restriction: openAccess
Self-archived version: publishedVersion


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