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

Tomasz M. Witkos, Wing Lee Chan, Merja Joensuu, Manuel Rhiel, Ed Pallister, Jane Thomas-Oates, A. Paul Mould, Alex A. Mironov, Christophe Biot, Yann Guerardel, Willy Morelle, Daniel Ungar, Felix T. Wieland, Eija Jokitalo, May Tassabehji, Uwe Kornak and Martin Lowe ()
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Tomasz M. Witkos: University of Manchester
Wing Lee Chan: Humboldt-Universität zu Berlin and Berlin Institute of Health
Merja Joensuu: University of Helsinki
Manuel Rhiel: Heidelberg University
Ed Pallister: University of York
Jane Thomas-Oates: University of York
A. Paul Mould: University of Manchester
Alex A. Mironov: University of Manchester
Christophe Biot: UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle
Yann Guerardel: UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle
Willy Morelle: UMR 8576 - UGSF - Unité de Glycobiologie Structurale et Fonctionnelle
Daniel Ungar: University of York
Felix T. Wieland: Heidelberg University
Eija Jokitalo: University of Helsinki
May Tassabehji: University of Manchester
Uwe Kornak: Humboldt-Universität zu Berlin and Berlin Institute of Health
Martin Lowe: University of Manchester

Nature Communications, 2019, vol. 10, issue 1, 1-18

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-08044-6

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