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J Biol Chem. 2015 Feb 6;290(6):3349-58. doi: 10.1074/jbc.M114.608174. Epub 2014 Dec 9.

Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth.

Author information

1
From the Institute of Vegetative Anatomy, Charité - Universitätsmedizin Berlin, 10115 Berlin, Germany, wenke.seifert@charite.de.
2
Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany, Max-Planck-Institute for Molecular Genetics, FG Development and Disease, 14195 Berlin, Germany.
3
Department of Molecular Pharmacology and Cell Biology, Leibniz-Institute for Molecular Pharmacology, 13125 Berlin, Germany.
4
From the Institute of Vegetative Anatomy, Charité - Universitätsmedizin Berlin, 10115 Berlin, Germany.
5
Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany, and the Division of Human Genetics, Innsbruck Medical University, A-6020 Innsbruck, Austria.
6
Institute for Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.

Abstract

Postnatal microcephaly, intellectual disability, and progressive retinal dystrophy are major features of autosomal recessive Cohen syndrome, which is caused by mutations in the gene COH1 (VPS13B). We have recently identified COH1 as a Golgi-enriched scaffold protein that contributes to the structural maintenance and function of the Golgi complex. Here, we show that association of COH1 with the Golgi complex depends on the small GTPase RAB6. RNAi-mediated knockdown of RAB6A/A' prevents the localization of COH1 to the Golgi complex. Expression of the constitutively inactive RAB6_T27N mutant led to an increased solubilization of COH1 from lipid membrane preparations. Co-IP experiments confirmed the physical interaction of COH1 with RAB6 that preferentially occurred with the constitutively active RAB6_Q72L mutants. Depletion of COH1 in primary neurons negatively interfered with neurite outgrowth, indicating a causal link between the integrity of the Golgi complex and axonal outgrowth. We conclude that COH1 is a RAB6 effector protein and that reduced brain size in Cohen syndrome patients likely results from impaired COH1 function at the Golgi complex, causing decreased neuritogenesis.

KEYWORDS:

COH1; Cohen Syndrome; GTPase; Genetic Disease; Golgi; Neurite Outgrowth; Protein-Protein Interaction; RAB6

PMID:
25492866
PMCID:
PMC4319006
DOI:
10.1074/jbc.M114.608174
[Indexed for MEDLINE]
Free PMC Article

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