1. GORAB scaffolds COPI at the trans-Golgi for efficient enzyme recycling and correct protein glycosylation
- Author
-
Witkos, Tomasz M., Chan, Wing Lee, Joensuu, Merja, Rhiel, Manuel, Pallister, Ed, Thomas-Oates, Jane, Mould, A. Paul, Mironov, Alex A., Biot, Christophe, Guerardel, Yann, Morelle, Willy, Ungar, Daniel, Wieland, Felix T., Jokitalo, Eija, Tassabehji, May, Kornak, Uwe, Lowe, Martin, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA), Department of Molecular Biology, Princeton University, HiLIFE - Institute of Biotechnology [Helsinki] (BI), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Faculty of Life Sciences [Manchester], University of Manchester [Manchester], Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Université de Lille-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Université de Lille, CNRS, University of Manchester Institute of Science and Technology [UMIST], Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Universität Heidelberg [Heidelberg] = Heidelberg University, Department of Chemistry [York, UK], Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF], Department of Biology [York], Electron Microscopy, Institute of Biotechnology, and Doctoral Programme in Integrative Life Science
- Subjects
Glycosylation ,119 Other natural sciences ,Science ,Golgi Apparatus ,Dwarfism ,Article ,Coat Protein Complex I ,ADP-RIBOSYLATION FACTOR ,RECESSIVE FORM ,OF-FUNCTION MUTATIONS ,Humans ,SCYL1 ,lcsh:Science ,BETA-COP ,Cells, Cultured ,ComputingMilieux_MISCELLANEOUS ,COATED VESICLES ,Bone Diseases ,Carrier Proteins ,Cells ,Cultured ,Enzymes ,Golgi Matrix Proteins ,HEK293 Cells ,HeLa Cells ,Mutation ,Protein Binding ,Protein Transport ,RNA Interference ,Skin Diseases ,Genetic ,Transcription Factors ,COMPLEX ,[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM] ,COATOMER ,Skin Diseases, Genetic ,GERODERMIA OSTEODYSPLASTICA ,DNA-Binding Proteins ,Adaptor Proteins, Vesicular Transport ,[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM] ,MEMBRANE TRAFFICKING ,lcsh:Q - Abstract
COPI is a key mediator of protein trafficking within the secretory pathway. COPI is recruited to the membrane primarily through binding to Arf GTPases, upon which it undergoes assembly to form coated transport intermediates responsible for trafficking numerous proteins, including Golgi-resident enzymes. Here, we identify GORAB, the protein mutated in the skin and bone disorder gerodermia osteodysplastica, as a component of the COPI machinery. GORAB forms stable domains at the trans-Golgi that, via interactions with the COPI-binding protein Scyl1, promote COPI recruitment to these domains. Pathogenic GORAB mutations perturb Scyl1 binding or GORAB assembly into domains, indicating the importance of these interactions. Loss of GORAB causes impairment of COPI-mediated retrieval of trans-Golgi enzymes, resulting in a deficit in glycosylation of secretory cargo proteins. Our results therefore identify GORAB as a COPI scaffolding factor, and support the view that defective protein glycosylation is a major disease mechanism in gerodermia osteodysplastica., COPI is recruited to the membrane by binding to Arf GTPases. Here the authors find that GORAB, a trans-Golgi protein, promotes COPI recruitment by forming membrane domains that also contain the COPI-interacting protein Scyl1, which is required for efficient glycosylation of cargo proteins.
- Published
- 2019