GORAB Missense Mutations Disrupt RAB6 and ARF5 Binding and Golgi Targeting

Egerer, Johannes; Emmerich, Denise; Fischer-Zirnsak, Björn; Chan, Wing Lee; Meierhofer, David; Tuysuz, Beyhan; Marschner, Katrin; Sauer, Sascha; Barr, Francis A.; Mundlos, Stefan; Kornak, Uwe

doi:10.1038/jid.2015.192

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GORAB Missense Mutations Disrupt RAB6 and ARF5 Binding and Golgi Targeting

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Egerer, Johannes
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

Emmerich, Denise
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

Fischer-Zirnsak, Björn
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

Chan, Wing Lee
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Meierhofer, David
Mass Spectrometry (Head: David Meierhofer), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Sauer, Sascha
Nutrigenomics and Gene Regulation (Sascha Sauer), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Mundlos, Stefan
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Kornak, Uwe
Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Egerer, J., Emmerich, D., Fischer-Zirnsak, B., Chan, W. L., Meierhofer, D., Tuysuz, B., et al. (2015). GORAB Missense Mutations Disrupt RAB6 and ARF5 Binding and Golgi Targeting. The Journal of Investigative Dermatology: an International Journal for Research in Cutaneous Biology, 135(10), 2368-2376. doi:10.1038/jid.2015.192.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0028-5E99-3

Abstract

Gerodermia osteodysplastica is a hereditary segmental progeroid disorder affecting skin, connective tissues, and bone that is caused by loss-of-function mutations in GORAB. The golgin, RAB6-interacting (GORAB) protein localizes to the Golgi apparatus and interacts with the small GTPase RAB6. In this study, we used different approaches to shed more light on the recruitment of GORAB to this compartment. We show that GORAB best colocalizes with trans-Golgi markers and is rapidly displaced upon Brefeldin A exposition, indicating a loose association with Golgi membranes. A yeast two-hybrid screening revealed a specific interaction with the small GTPase ADP-ribosylation factor (ARF5) in its active, GTP-bound form. ARF5 and RAB6 bind to GORAB via the same internal Golgi-targeting RAB6 and ARF5 binding (IGRAB) domain. Two GORAB missense mutations identified in gerodermia osteodysplastica patients fall within this IGRAB domain. GORAB carrying the mutation p.Ala220Pro had a cytoplasmic distribution and failed to interact with both RAB6 and ARF5. In contrast, the p.Ser175Phe mutation displaced GORAB from the Golgi compartment to vesicular structures and selectively impaired ARF5 binding. Our findings indicate that the IGRAB domain is crucial for the Golgi localization of GORAB and that loss of this localization impairs its physiological function.