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

Tomasz Maciej Witkos; Wing Lee Chan; Merja Joensuu; Ed Pallister; Jane Thomas-Oates; AP Mould; Aleksandr Mironov; Christophe Biot; Yann Guerardel; Willy Morelle; Daniel Ungar; Felix T. Wieland; Eija Jokitalo; Mayada Tassabehji; Uwe Kornak; Martin Lowe

doi:10.1038/s41467-018-08044-6

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

Tomasz Maciej Witkos, Wing Lee Chan, Merja Joensuu, Ed Pallister, Jane Thomas-Oates, AP Mould, Aleksandr Mironov, Christophe Biot, Yann Guerardel, Willy Morelle, Daniel Ungar, Felix T. Wieland, Eija Jokitalo, Mayada Tassabehji, Uwe Kornak, Martin Lowe

Research output: Contribution to journal › Article › peer-review

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
major disease mechanism in gerodermia osteodysplastica.

Original language	English
Article number	127
Journal	Nat Commun
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-08044-6
Publication status	Published - 10 Jan 2019

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Witkos, T. M., Chan, W. L., Joensuu, M., Pallister, E., Thomas-Oates, J., Mould, AP., Mironov, A., Biot, C., Guerardel, Y., Morelle, W., Ungar, D., Wieland, F. T., Jokitalo, E., Tassabehji, M., Kornak, U., & Lowe, M. (2019). GORAB scaffolds COPI at the trans-Golgi for efficient enzyme recycling and correct protein glycosylation. Nat Commun, 10(1), Article 127. https://doi.org/10.1038/s41467-018-08044-6

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

abstract = "COPI is a key mediator of protein trafficking within the secretory pathway. COPIis recruited to the membrane primarily through binding to Arf GTPases, uponwhich it undergoes assembly to form coated transport intermediates responsiblefor trafficking numerous proteins, including Golgi-resident enzymes. Here, weidentify GORAB, the protein mutated in the skin and bone disorder gerodermiaosteodysplastica, as a component of the COPI machinery. GORAB forms stabledomains at the trans-Golgi that, via interactions with the COPI-binding proteinScyl1, promote COPI recruitment to these domains. Pathogenic GORABmutations perturb Scyl1 binding or GORAB assembly into domains, indicatingthe importance of these interactions. Loss of GORAB causes impairment of COPI mediated retrieval of trans-Golgi enzymes, resulting in a deficit in glycosylationof secretory cargo proteins. Our results therefore identify GORAB as a COPIscaffolding factor, and support the view that defective protein glycosylation ismajor disease mechanism in gerodermia osteodysplastica.",

author = "Witkos, {Tomasz Maciej} and Chan, {Wing Lee} and Merja Joensuu and Ed Pallister and Jane Thomas-Oates and AP Mould and Aleksandr Mironov and Christophe Biot and Yann Guerardel and Willy Morelle and Daniel Ungar and Wieland, {Felix T.} and Eija Jokitalo and Mayada Tassabehji and Uwe Kornak and Martin Lowe",

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doi = "10.1038/s41467-018-08044-6",

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Witkos, TM, Chan, WL, Joensuu, M, Pallister, E, Thomas-Oates, J, Mould, AP, Mironov, A, Biot, C, Guerardel, Y, Morelle, W, Ungar, D, Wieland, FT, Jokitalo, E, Tassabehji, M, Kornak, U & Lowe, M 2019, 'GORAB scaffolds COPI at the trans-Golgi for efficient enzyme recycling and correct protein glycosylation', Nat Commun, vol. 10, no. 1, 127. https://doi.org/10.1038/s41467-018-08044-6

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T1 - GORAB scaffolds COPI at the trans-Golgi for efficient enzyme recycling and correct protein glycosylation

AU - Witkos, Tomasz Maciej

AU - Chan, Wing Lee

AU - Joensuu, Merja

AU - Pallister, Ed

AU - Thomas-Oates, Jane

AU - Mould, AP

AU - Mironov, Aleksandr

AU - Biot, Christophe

AU - Guerardel, Yann

AU - Morelle, Willy

AU - Ungar, Daniel

AU - Wieland, Felix T.

AU - Jokitalo, Eija

AU - Tassabehji, Mayada

AU - Kornak, Uwe

AU - Lowe, Martin

PY - 2019/1/10

Y1 - 2019/1/10

N2 - COPI is a key mediator of protein trafficking within the secretory pathway. COPIis recruited to the membrane primarily through binding to Arf GTPases, uponwhich it undergoes assembly to form coated transport intermediates responsiblefor trafficking numerous proteins, including Golgi-resident enzymes. Here, weidentify GORAB, the protein mutated in the skin and bone disorder gerodermiaosteodysplastica, as a component of the COPI machinery. GORAB forms stabledomains at the trans-Golgi that, via interactions with the COPI-binding proteinScyl1, promote COPI recruitment to these domains. Pathogenic GORABmutations perturb Scyl1 binding or GORAB assembly into domains, indicatingthe importance of these interactions. Loss of GORAB causes impairment of COPI mediated retrieval of trans-Golgi enzymes, resulting in a deficit in glycosylationof secretory cargo proteins. Our results therefore identify GORAB as a COPIscaffolding factor, and support the view that defective protein glycosylation ismajor disease mechanism in gerodermia osteodysplastica.

AB - COPI is a key mediator of protein trafficking within the secretory pathway. COPIis recruited to the membrane primarily through binding to Arf GTPases, uponwhich it undergoes assembly to form coated transport intermediates responsiblefor trafficking numerous proteins, including Golgi-resident enzymes. Here, weidentify GORAB, the protein mutated in the skin and bone disorder gerodermiaosteodysplastica, as a component of the COPI machinery. GORAB forms stabledomains at the trans-Golgi that, via interactions with the COPI-binding proteinScyl1, promote COPI recruitment to these domains. Pathogenic GORABmutations perturb Scyl1 binding or GORAB assembly into domains, indicatingthe importance of these interactions. Loss of GORAB causes impairment of COPI mediated retrieval of trans-Golgi enzymes, resulting in a deficit in glycosylationof secretory cargo proteins. Our results therefore identify GORAB as a COPIscaffolding factor, and support the view that defective protein glycosylation ismajor disease mechanism in gerodermia osteodysplastica.

U2 - 10.1038/s41467-018-08044-6

DO - 10.1038/s41467-018-08044-6

M3 - Article

C2 - 30631079

SN - 2041-1723

VL - 10

JO - Nat Commun

JF - Nat Commun

IS - 1

M1 - 127

ER -

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

Abstract

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