GORAB scaffolds COPI at the trans-Golgi for efficient enzyme recycling and correct protein glycosylation

• Published in: Nature communications Vol. 10; no. 1; p. 127
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10-01-2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/109; 13/31; 14; 14/28; 14/63; 631/80/221; 631/80/304; 631/80/313/1525; 82/103; 82/111; 82/80; Adaptor Proteins, Vesicular Transport; Assembly; Biochemistry; Biochemistry, Molecular Biology; Biocompatibility; Biomedical materials; Bone Diseases - congenital; Bone Diseases - genetics; Bone Diseases - metabolism; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cells, Cultured; Coat Protein Complex I - genetics; Coat Protein Complex I - metabolism; DNA-Binding Proteins; Domains; Dwarfism - genetics; Dwarfism - metabolism; Enzymes; Enzymes - metabolism; Glycosylation; Golgi apparatus; Golgi Apparatus - metabolism; Golgi Matrix Proteins; HEK293 Cells; HeLa Cells; Humanities and Social Sciences; Humans; Intermediates; Life Sciences; multidisciplinary; Mutation; Protein Binding; Protein Transport; Proteins; RNA Interference; Scaffolding; Science; Science (multidisciplinary); Skin; Skin Diseases, Genetic - genetics; Skin Diseases, Genetic - metabolism; Structural Biology; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-08044-6

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.