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J. Biol. Chem., Vol. 279, Issue 37, 38626-38635, September 10, 2004

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Homo-oligomerization of ALS2 through Its Unique Carboxyl-terminal Regions Is Essential for the ALS2-associated Rab5 Guanine Nucleotide Exchange Activity and Its Regulatory Function on Endosome Trafficking^*

Ryota Kunita, Asako Otomo¶, Hikaru Mizumura, Kyoko Suzuki, Junko Showguchi-Miyata, Yoshiko Yanagisawa, Shinji Hadano, and Joh-E Ikeda||**

From the Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, (Tokai University School of Medicine), the Department of Molecular Neuroscience, The Institute of Medical Sciences, Tokai University, Isehara, Kanagawa 259-1193, Japan and the ^||Department of Paediatrics, Faculty of Medicine, University of Ottawa, Ontario K1H 8M5, Canada

Mutations in the ALS2 gene have been known to account for a juvenile recessive form of amyotrophic lateral sclerosis (ALS2), a rare juvenile recessive form of primary lateral sclerosis, and a form of hereditary spastic paraplegia (HSP), indicating that the ALS2 protein is essential for the maintenance of motor neurons. Recently, we have demonstrated that the ALS2 protein specifically binds to the small GTPase Rab5 and acts as a GEF (guanine nucleotide exchange factor) for Rab5. We have also shown that its Rab5GEF-requisite domain resides within the C-terminal 640-amino acid region spanning membrane occupation and recognition nexus motifs and the vacuolar protein sorting 9 domain. Transiently expressed ALS2 localized onto early endosomal compartments and stimulated endosome fusions in neuronal and non-neuronal cells in an Rab5GEF activity-dependent manner. These results indicate that the C-terminal region of ALS2 plays a crucial role in endosomal dynamics by its Rab5GEF activity. Here we delineate a molecular feature of the ALS2-associated function through the C-terminal region-mediated homo-oligomerization. A yeast two-hybrid screen for interacting proteins with the ALS2 C-terminal portion identified ALS2 itself. ALS2 forms a homophilic oligomer through its distinct C-terminal regions. This homo-oligomerization is crucial for the Rab5GEF activity in vitro and the ALS2-mediated endosome enlargement in the cells. Taken together, these results indicate that oligomerization of the ALS2 protein is one of the fundamental features for its physiological function involving endosome dynamics in vivo.

Received for publication, June 2, 2004

^* This work was supported in part by the Japan Science and Technology Agency (to J.-E. I.), and in part by research grants from Research on Psychiatric and Neurological Diseases and Mental Health from the Ministry of Health, Labour and Welfare (to J.-E. I.), a Grantin-aid for Scientific Research from Japan Society for the Promotion of Science (to S. H.), the Sumitomo Foundation (to S. H.), and the Naito Foundation (to S. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by a Research Fellowship for Young Scientist from the Japan Society of the Promotion of Science.

^** To whom correspondence should be addressed: Dept. of Molecular Neuroscience, Inst. of Medical Sciences, Tokai University, Isehara, Kanagawa 259-1193, Japan. Tel.: 81-463-91-5095; Fax: 81-463-91-4993; E-mail: joh-e{at}nga.med.u-tokai.ac.jp.

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