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

[Image: see text] 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...

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Autores principales: Zhou, Kecheng, Dichlberger, Andrea, Martinez-Seara, Hector, Nyholm, Thomas K. M., Li, Shiqian, Kim, Young Ah, Vattulainen, Ilpo, Ikonen, Elina, Blom, Tomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2018
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968438/
https://www.ncbi.nlm.nih.gov/pubmed/29806001
http://dx.doi.org/10.1021/acscentsci.7b00582
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author Zhou, Kecheng
Dichlberger, Andrea
Martinez-Seara, Hector
Nyholm, Thomas K. M.
Li, Shiqian
Kim, Young Ah
Vattulainen, Ilpo
Ikonen, Elina
Blom, Tomas
author_facet Zhou, Kecheng
Dichlberger, Andrea
Martinez-Seara, Hector
Nyholm, Thomas K. M.
Li, Shiqian
Kim, Young Ah
Vattulainen, Ilpo
Ikonen, Elina
Blom, Tomas
author_sort Zhou, Kecheng
collection PubMed
description [Image: see text] 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.
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spelling pubmed-59684382018-05-27 A Ceramide-Regulated Element in the Late Endosomal Protein LAPTM4B Controls Amino Acid Transporter Interaction Zhou, Kecheng Dichlberger, Andrea Martinez-Seara, Hector Nyholm, Thomas K. M. Li, Shiqian Kim, Young Ah Vattulainen, Ilpo Ikonen, Elina Blom, Tomas ACS Cent Sci [Image: see text] 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. American Chemical Society 2018-05-09 2018-05-23 /pmc/articles/PMC5968438/ /pubmed/29806001 http://dx.doi.org/10.1021/acscentsci.7b00582 Text en Copyright © 2018 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Zhou, Kecheng
Dichlberger, Andrea
Martinez-Seara, Hector
Nyholm, Thomas K. M.
Li, Shiqian
Kim, Young Ah
Vattulainen, Ilpo
Ikonen, Elina
Blom, Tomas
A Ceramide-Regulated Element in the Late Endosomal Protein LAPTM4B Controls Amino Acid Transporter Interaction
title A Ceramide-Regulated Element in the Late Endosomal Protein LAPTM4B Controls Amino Acid Transporter Interaction
title_full A Ceramide-Regulated Element in the Late Endosomal Protein LAPTM4B Controls Amino Acid Transporter Interaction
title_fullStr A Ceramide-Regulated Element in the Late Endosomal Protein LAPTM4B Controls Amino Acid Transporter Interaction
title_full_unstemmed A Ceramide-Regulated Element in the Late Endosomal Protein LAPTM4B Controls Amino Acid Transporter Interaction
title_short A Ceramide-Regulated Element in the Late Endosomal Protein LAPTM4B Controls Amino Acid Transporter Interaction
title_sort ceramide-regulated element in the late endosomal protein laptm4b controls amino acid transporter interaction
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968438/
https://www.ncbi.nlm.nih.gov/pubmed/29806001
http://dx.doi.org/10.1021/acscentsci.7b00582
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