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Structural basis of human PDZD8–Rab7 interaction for the ER-late endosome tethering

The membrane contact sites (MCSs) between the ER and late endosomes (LEs) are essential for the regulation of endosomal protein sorting, dynamics, and motility. PDZD8 is an ER transmembrane protein containing a Synaptotagmin-like Mitochondrial lipid-binding Proteins (SMP) domain. PDZD8 tethers the E...

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Autores principales: Khan, Haider, Chen, Lin, Tan, Lingchen, Im, Young Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458453/
https://www.ncbi.nlm.nih.gov/pubmed/34552186
http://dx.doi.org/10.1038/s41598-021-98419-5
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author Khan, Haider
Chen, Lin
Tan, Lingchen
Im, Young Jun
author_facet Khan, Haider
Chen, Lin
Tan, Lingchen
Im, Young Jun
author_sort Khan, Haider
collection PubMed
description The membrane contact sites (MCSs) between the ER and late endosomes (LEs) are essential for the regulation of endosomal protein sorting, dynamics, and motility. PDZD8 is an ER transmembrane protein containing a Synaptotagmin-like Mitochondrial lipid-binding Proteins (SMP) domain. PDZD8 tethers the ER to late endosomes and lysosomes by associating its C-terminal coiled-coil (CC) with the LE Rab7. To identify the structural determinants for the PDZD8–Rab7 interaction, we determined the crystal structure of the human PDZD8 CC domain in complex with the GTP-bound form of Rab7. The PDZD8 CC contains one short helix and the two helices forming an antiparallel coiled-coil. Two Rab7 molecules bind to the opposite sides of the PDZD8 CC in a 2:1 ratio. The switch I/II and interswitch regions of the GTP-loaded Rab7 form the binding interfaces, which correlates with the GTP-dependent interaction of PDZD8 and Rab7. Analysis of the protein interaction by isothermal titration calorimetry confirms that two Rab7 molecules bind the PDZD8 CC in a GTP-dependent manner. The structural model of the PDZD8 CC–Rab7 complex correlates with the recruitment of PDZD8 at the LE–ER interface and its role in lipid transport and regulation.
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spelling pubmed-84584532021-09-24 Structural basis of human PDZD8–Rab7 interaction for the ER-late endosome tethering Khan, Haider Chen, Lin Tan, Lingchen Im, Young Jun Sci Rep Article The membrane contact sites (MCSs) between the ER and late endosomes (LEs) are essential for the regulation of endosomal protein sorting, dynamics, and motility. PDZD8 is an ER transmembrane protein containing a Synaptotagmin-like Mitochondrial lipid-binding Proteins (SMP) domain. PDZD8 tethers the ER to late endosomes and lysosomes by associating its C-terminal coiled-coil (CC) with the LE Rab7. To identify the structural determinants for the PDZD8–Rab7 interaction, we determined the crystal structure of the human PDZD8 CC domain in complex with the GTP-bound form of Rab7. The PDZD8 CC contains one short helix and the two helices forming an antiparallel coiled-coil. Two Rab7 molecules bind to the opposite sides of the PDZD8 CC in a 2:1 ratio. The switch I/II and interswitch regions of the GTP-loaded Rab7 form the binding interfaces, which correlates with the GTP-dependent interaction of PDZD8 and Rab7. Analysis of the protein interaction by isothermal titration calorimetry confirms that two Rab7 molecules bind the PDZD8 CC in a GTP-dependent manner. The structural model of the PDZD8 CC–Rab7 complex correlates with the recruitment of PDZD8 at the LE–ER interface and its role in lipid transport and regulation. Nature Publishing Group UK 2021-09-22 /pmc/articles/PMC8458453/ /pubmed/34552186 http://dx.doi.org/10.1038/s41598-021-98419-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Khan, Haider
Chen, Lin
Tan, Lingchen
Im, Young Jun
Structural basis of human PDZD8–Rab7 interaction for the ER-late endosome tethering
title Structural basis of human PDZD8–Rab7 interaction for the ER-late endosome tethering
title_full Structural basis of human PDZD8–Rab7 interaction for the ER-late endosome tethering
title_fullStr Structural basis of human PDZD8–Rab7 interaction for the ER-late endosome tethering
title_full_unstemmed Structural basis of human PDZD8–Rab7 interaction for the ER-late endosome tethering
title_short Structural basis of human PDZD8–Rab7 interaction for the ER-late endosome tethering
title_sort structural basis of human pdzd8–rab7 interaction for the er-late endosome tethering
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8458453/
https://www.ncbi.nlm.nih.gov/pubmed/34552186
http://dx.doi.org/10.1038/s41598-021-98419-5
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