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  GORAB Missense Mutations Disrupt RAB6 and ARF5 Binding and Golgi Targeting

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.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-5E99-3 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0028-5E9A-1
Genre: Journal Article

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 Creators:
Egerer, Johannes1, Author
Emmerich, Denise1, Author
Fischer-Zirnsak, Björn1, Author
Chan, Wing Lee 1, Author
Meierhofer, David2, Author              
Tuysuz, Beyhan , Author
Marschner, Katrin, Author
Sauer, Sascha3, Author              
Barr, Francis A. , Author
Mundlos, Stefan1, Author              
Kornak, Uwe1, Author              
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Mass Spectrometry (Head: David Meierhofer), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479669              
3Nutrigenomics and Gene Regulation (Sascha Sauer), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479662              

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 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.

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Language(s): eng - English
 Dates: 2015-05-222015-10
 Publication Status: Published in print
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 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1038/jid.2015.192
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Title: The Journal of Investigative Dermatology : an International Journal for Research in Cutaneous Biology
  Other : J Invest Dermatol
Source Genre: Journal
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Publ. Info: New York, NY [etc.] : Elsevier Science Pub. Co. [etc.]
Pages: - Volume / Issue: 135 (10) Sequence Number: - Start / End Page: 2368 - 2376 Identifier: ISSN: 0022-202X
CoNE: https://pure.mpg.de/cone/journals/resource/954925414921