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

Abstract 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 teth...

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Autores principales:	Haider Khan, Lin Chen, Lingchen Tan, Young Jun Im
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c356627450f1438195c4b1d42f67f384
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spelling	oai:doaj.org-article:c356627450f1438195c4b1d42f67f3842021-12-02T18:14:30ZStructural basis of human PDZD8–Rab7 interaction for the ER-late endosome tethering10.1038/s41598-021-98419-52045-2322https://doaj.org/article/c356627450f1438195c4b1d42f67f3842021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-98419-5https://doaj.org/toc/2045-2322Abstract 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.Haider KhanLin ChenLingchen TanYoung Jun ImNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Haider Khan Lin Chen Lingchen Tan Young Jun Im Structural basis of human PDZD8–Rab7 interaction for the ER-late endosome tethering
description	Abstract 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.
format	article
author	Haider Khan Lin Chen Lingchen Tan Young Jun Im
author_facet	Haider Khan Lin Chen Lingchen Tan Young Jun Im
author_sort	Haider Khan
title	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_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_sort	structural basis of human pdzd8–rab7 interaction for the er-late endosome tethering
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/c356627450f1438195c4b1d42f67f384
work_keys_str_mv	AT haiderkhan structuralbasisofhumanpdzd8rab7interactionfortheerlateendosometethering AT linchen structuralbasisofhumanpdzd8rab7interactionfortheerlateendosometethering AT lingchentan structuralbasisofhumanpdzd8rab7interactionfortheerlateendosometethering AT youngjunim structuralbasisofhumanpdzd8rab7interactionfortheerlateendosometethering
_version_	1718378418797543424

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

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