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

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. 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. ALS2 was initially identified as a causative gene for a juvenile recessive form of amyotrophic lateral sclerosis (ALS2), 1The abbreviations used are: ALS2, amyotrophic lateral sclerosis 2; PLS, primary lateral sclerosis; HSP, hereditary spastic paraplegia; IAHSP, infantile-onset ascending hereditary spastic paralysis; GEF, guanine nucleotide exchange factor; aa, amino acid residues; MORN, membrane occupation and recognition nexus; RLD, RCC1-like domain; DH, Dbl homology; PH, pleckstrin homology; VPS9, vacuolar protein sorting 9; Y2H, yeast two-hybrid; CHAPS, 3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonic acid; EEA1, early endosome (auto) antigen 1; EGFP, enhanced green fluorescent protein; WT, wild type; HA, hemagglutinin; Rab5, Ras-related in brain 5; PFA, paraformaldehyde.1The abbreviations used are: ALS2, amyotrophic lateral sclerosis 2; PLS, primary lateral sclerosis; HSP, hereditary spastic paraplegia; IAHSP, infantile-onset ascending hereditary spastic paralysis; GEF, guanine nucleotide exchange factor; aa, amino acid residues; MORN, membrane occupation and recognition nexus; RLD, RCC1-like domain; DH, Dbl homology; PH, pleckstrin homology; VPS9, vacuolar protein sorting 9; Y2H, yeast two-hybrid; CHAPS, 3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonic acid; EEA1, early endosome (auto) antigen 1; EGFP, enhanced green fluorescent protein; WT, wild type; HA, hemagglutinin; Rab5, Ras-related in brain 5; PFA, paraformaldehyde. and a rare juvenile recessive form of primary lateral sclerosis (PLSJ) (1Hadano S. Hand C.K. Osuga H. Yanagisawa Y. Otomo A. Devon R.S. Miyamoto N. Showguchi-Miyata J. Okada Y. Singaraja R. Figlewicz D.A. Kwiatkowski T. Hosler B.A. Sagie T. Skaug J. Nasir J. Brown Jr., R.H. Scherer S.W. Rouleau G.A. Hayden M.R. Ikeda J.-E. Nat. Genet. 2001; 29: 166-173Crossref PubMed Scopus (581) Google Scholar, 2Yang Y. Hentati A. Deng H.X. Dabbagh O. Sasaki T. Hirano M. Hung W.Y. Ouahchi K. Yan J. Azim A.C. Cole N. Gascon G. Yagmour A. Ben-Hamida M. Pericak-Vance M. Hentati F. Siddique T. Nat. Genet. 2001; 29: 160-165Crossref PubMed Scopus (653) Google Scholar). ALS2 is characterized by a loss of upper motor neurons and spasticity of limb and facial muscles occasionally associated with several signs of lower motor neuron defects (3Ben Hamida M. Hentati F. Ben Hamida C. Brain. 1990; 113: 347-363Crossref PubMed Scopus (154) Google Scholar), whereas PLSJ affects only upper motor neurons (4Lerman-Sagie T. Filiano J. Smith D.W. Korson M. J. Child. Neurol. 1996; 11: 54-57Crossref PubMed Scopus (35) Google Scholar). Recently, several independent homozygous ALS2 mutations have been found in families segregating an infantile-onset ascending hereditary spastic paralysis (IAHSP) (5Eymard-Pierre E. Lesca G. Dollet G. Santorelli F.M. di Capua M. Bertini E. Boespflug-Tanguy O. Am. J. Hum. Genet. 2002; 71: 518-527Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar, 6Lesca G. Eymard-Pierre E. Santorelli F.M. Cusmai R. di Capupa M. Valente E.M. Attia-Sobol J. Plauchu H. Leuzzi V. Ponzone A. Boespflug-Tanguy O. Bertini E. Neurology. 2003; 60: 674-682Crossref PubMed Scopus (55) Google Scholar, 7Devon R.S. Helm J.R. Roulean G.A. Leitner Y. Lerman-Sagie T. Lev D. Hayden M.R. Clin. Genet. 2003; 64: 210-215Crossref PubMed Scopus (87) Google Scholar) and a single family of a recessive complicated hereditary spastic paraplegia (HSP) (8Gros-Louis F. Meijer I.A. Hand C.K. Dube M.P. MacGregor D.L. Seni M.H. Devon R.S. Hayden M.R. Andermann F. Andermann E. Rouleau G.A. Ann. Neurol. 2003; 53: 144-145Crossref PubMed Scopus (96) Google Scholar). Thus, ALS2 mutations account for a number of juvenile recessive motor neuron diseases, indicating that the ALS2 protein plays an important role in the maintenance and/or survival of motor neurons. The ALS2 gene encodes a protein of 1657 amino acid residues (aa), which contains three putative guanine nucleotide exchange factor (GEF) domains (1Hadano S. Hand C.K. Osuga H. Yanagisawa Y. Otomo A. Devon R.S. Miyamoto N. Showguchi-Miyata J. Okada Y. Singaraja R. Figlewicz D.A. Kwiatkowski T. Hosler B.A. Sagie T. Skaug J. Nasir J. Brown Jr., R.H. Scherer S.W. Rouleau G.A. Hayden M.R. Ikeda J.-E. Nat. Genet. 2001; 29: 166-173Crossref PubMed Scopus (581) Google Scholar, 2Yang Y. Hentati A. Deng H.X. Dabbagh O. Sasaki T. Hirano M. Hung W.Y. Ouahchi K. Yan J. Azim A.C. Cole N. Gascon G. Yagmour A. Ben-Hamida M. Pericak-Vance M. Hentati F. Siddique T. Nat. Genet. 2001; 29: 160-165Crossref PubMed Scopus (653) Google Scholar). The N-terminal half of the ALS2 protein shares with of M. R. N. T. M. H. K. T. S. T. K. T. PubMed Scopus Google Scholar), and region is to as an RCC1-like domain which been found in a number of proteins S. M. J. 1996; Scopus Google Scholar, E. S. R. F. PubMed Scopus Google Scholar, C. S. E. F. R. 2003; PubMed Scopus Google Scholar, J. A. C. J. 2002; PubMed Scopus Google Scholar). acts as a GEF for GTPase M. R. N. T. M. H. K. T. S. T. K. T. PubMed Scopus Google Scholar), the for domains is by a of Dbl and pleckstrin which is a for for A. A. 2002; PubMed Scopus Google Scholar). The C-terminal of ALS2 a vacuolar protein sorting 9 which been found in Rab5 in brain 1996; PubMed Scopus Google Scholar), H. R. M. H. V. M. K. M. M. Full Text Full Text PDF PubMed Scopus Google Scholar), D. A. D. M. H. O. J. S. A. PubMed Scopus Google Scholar, 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), K. J. H. K. H. T. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), and H. K. K. K. Y. H. T. J. 2003; PubMed Scopus Google Scholar). membrane occupation and recognition nexus motifs H. S. M. M. K. Full Text Full Text PDF PubMed Google Scholar) in the region and The small a of fundamental and membrane M. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, S. A. 2002; PubMed Scopus Google Scholar, M. 2002; PubMed Scopus Google Scholar, J. A. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, Nat. PubMed Scopus Google Scholar, Nat. 2002; PubMed Scopus Google Scholar, M. H. Nat. 2001; PubMed Scopus Google Scholar). as and M. H. Nat. 2001; PubMed Scopus Google Scholar). known to the small by the of in exchange for A. 2001; PubMed Scopus Google Scholar). of GEF domains of ALS2, to as an of small We have demonstrated that one of three GEF VPS9, as an essential for the ALS2-associated Rab5GEF activity A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar). Transiently expressed ALS2 localized onto early endosomal compartments and the enlargement of in primary neurons A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar). of the ALS2 which as a the enlargement of A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar). and endosome A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar), that the Rab5GEF activity is We have also shown that the domain for the Rab5GEF activity resides within the C-terminal region spanning and these is that the region of ALS2 is one of the domains for the ALS2-mediated endosome dynamics in vivo. the molecular by which the ALS2 C-terminal region in early of the is an the molecular in we the C-terminal proteins by a the ALS2 protein was identified as an for the C-terminal region of we delineate the molecular of the ALS2 and its in the Rab5GEF activity as as endosomal that was by distinct C-terminal of which within the and demonstrated that ALS2 in cells. The ALS2 the Rab5GEF activity in vitro and its endosomal in the the of its to in Thus, the is to Rab5, ALS2 oligomer an important for the ALS2-associated Rab5GEF activity. these that ALS2 homo-oligomerization is crucial for its physiological function involving endosome and and endosome antigen and was with the by an the of and ALS2 proteins and of the used in by the the the The of the as as the in by the the of ALS2 and to and in vitro GEF and in vitro the of ALS2 and a the the of the The and also A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar). forms of ALS2, and by a by the ALS2 which the the enhanced green fluorescent protein ALS2 proteins and by the ALS2 forms of the screen was to the by the A brain in the was with as a the yeast was with and with a brain and by of the and the and and cells in with and by to the cells with and/or the cells with and in A of and of of the for by for by with A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar). The three with the A of of the used for with the in by and onto the membrane The with in for and with the by by the and of ALS2 and ALS2 and domain as A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar). The ALS2 proteins to the in the in for the GEF in vitro A portion of the proteins was to with by with to the of proteins the and proteins the in of and with for of was to a that was with was a of with a of to with The of the was with the of and GEF in vitro GEF was as A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar). the ALS2 proteins by the cells with the The small GTPase was also as A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar). of the was to the in vitro exchange in the of of the ALS2 The of Rab5 to the ALS2 was with of the ALS2 proteins in of the GEF of CHAPS, for with the the with for and to with and as A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar). cells with with with in for by with in for in and to the cells and for was as a to of with to and by of the ALS2 we have the ALS2 protein is to in endosomal dynamics in through the Rab5GEF activity by the C-terminal region of The of ALS2 A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar). is the domains the role in endosomal the molecular in we a brain for the C-terminal proteins by the A screen with as a independent that with of these the the C-terminal of the ALS2 protein and These results indicate that ALS2 is for the ALS2 in the the to for in yeast we and used in the a we found that distinct C-terminal of ALS2 by motifs and essential for the in yeast the a with the of the N-terminal portion of the motifs the with together, these results that distinct of ALS2, and for the ALS2 in yeast whereas motifs and the domain for of the ALS2 in the ALS2 proteins with in we We with cells and the shown in was with was also in the with with with the results of the which of the region for the in was also with These results that ALS2 proteins with through C-terminal that in cells. of the ALS2 the ALS2 protein as a form in the we a We the and proteins cells with ALS2 proteins to a and the by with shown in in and in molecular of and A and These molecular indicate that ALS2 is to form a homophilic oligomer a in the N-terminal and domains also in the as the ALS2 the C-terminal region of ALS2 the region for is also that forms for and in the A and proteins with and in of the Taken together, these results that ALS2 as homophilic in vivo. The for the ALS2 in to the for the oligomerization in we the of ALS2, and We also the the domain as a of the which cells in with one of the and in with that the proteins by and as in the of This that the for the and the with Thus, the region by the motifs and the domain is to the ALS2 whereas the motifs and the which essential for the ALS2-associated Rab5GEF activity A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar), for with the results by the the for the ALS2 oligomerization within the region by motifs and we for residues to one of the region ALS2 and a identified A. K. R. Y. J. H. and J.-E. in the with which was by the ALS2 the A. K. R. Y. J. H. and J.-E. the to with that crucial for the ALS2 The was also with in the in which the the was for the ALS2 in yeast Taken together, results indicate that a domain that is essential for the ALS2 of the ALS2 for Rab5 GEF in the oligomerization of ALS2 through its C-terminal region is in its Rab5GEF we the in vitro GEF We the wild and ALS2 proteins cells and the in vitro exchange of We a of the ALS2 protein in cells the ALS2 of ALS2 the GEF activity in vitro we have shown A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar), and of which stimulated the N-terminal of Rab5GEF activity the ALS2 the its GEF activity Thus, of the which for for the Rab5GEF activity. a of by the of motifs one by one that the of of motifs for its GEF activity which the to with activity in the of the ALS2 of its GEF activity We also found that which the the and the essential for the oligomerization Rab5GEF indicating that the amino acid residues also crucial for the ALS2-associated Rab5GEF activity. These results several important the the and the region spanning which one of the essential for the ALS2 is essential for its Rab5GEF activity in to the and ALS2 loss of Rab5GEF activity in the ALS2 as and a in to Rab5, we in vitro The in vitro the the in the of We used the form of in ALS2 to the form of to the forms A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google a with with results A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar). also to whereas as as with Thus, ALS2 the to ALS2 the to the and the to with that the and domains essential for the that the domain of ALS2 binds to Rab5, its Rab5GEF activity. a the for homo-oligomerization and the Rab5GEF to This that oligomerization is an essential feature for for the to the activity. an and also to with is that a in the Rab5GEF activity in a number of ALS2 is to a loss of its to indicating that the of ALS2 with Rab5 is a for the ALS2-associated Rab5GEF activity. by a of ALS2 in a Rab5GEF and delineate the of the ALS2 oligomerization as as the ALS2-associated Rab5GEF activity in we the of of a form of ALS2 with an the in cells. we have shown that of domains endosome enlargement in cells A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar). We found that also function as a form and activity endosome by in cells. A. H. K. S. and J.-E. we to of as a form in and to the of mutations in the of endosome we the the in cells. We that the ALS2 also shown in of in and of that early we the of the ALS2 the endosome in cells. results that the of the early endosome ALS2 also localized onto the the and compartments of the also demonstrated that its to the endosome with results and A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar). these results indicate that the oligomerization of ALS2 for the Rab5GEF activity is crucial for the endosome enlargement by of forms of ALS2 in the and in the Rab5GEF activity associated with ALS2 an essential feature for the ALS2-associated physiological function endosome We have demonstrated that the ALS2 protein is in endosomal dynamics through its Rab5GEF activity by the C-terminal domains A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar). we for the that ALS2 forms a through its C-terminal region and that oligomerization is essential for the ALS2-associated Rab5GEF activity and its function endosome as endosome and that the expressed ALS2 protein a an in the cells. was also the form of ALS2 was used ALS2 was with ALS2 the C-terminal region These results that the ALS2 protein as an form in vivo. we also the for the ALS2 homo-oligomerization by and ALS2 The results that distinct and oligomerization by interacting with These within the region by motifs and domain known motifs and/or domains have been the region the crucial residues the for the ALS2 of portion the we have to the of the ALS2 and to as proteins in the and these proteins by as to as in the cells. for the ALS2 oligomerization is that the ALS2 in an form an and the that ALS2 form an the for the ALS2 protein we also the important the by the oligomerization of ALS2 and its associated Rab5GEF activity in We have shown that the C-terminal region spanning and the domain of ALS2 of the region for the ALS2-associated Rab5GEF activity A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar). results in with the that a number of the ALS2-associated Rab5GEF activity within the C-terminal only the motifs and domain A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar) also as and one of these to was found to the region for the ALS2 This that the ALS2 homo-oligomerization one of the for the ALS2-associated Rab5GEF activity a molecular feature the physiological function for ALS2 in vivo. in vitro GEF activity that the ALS2 Rab5GEF these ALS2 to form the that oligomerization is to Rab5. the as as ALS2 proteins to of the Rab5GEF activity and/or the oligomerization that is also a for the ALS2-associated Rab5GEF activity. Taken together, is that the of the ALS2 protein ALS2 and the of the important for its Rab5GEF activity by the C-terminal region of to the region for the ALS2-associated GEF J. Full Text Full Text PDF PubMed Scopus Google Scholar) have the in which the C-terminal portion of ALS2 motifs as as the region crucial for the oligomerization in Rab5GEF activity in the ALS2 the the ALS2-associated Rab5GEF activity. is that a of the for the of the ALS2 in the ALS2-associated Rab5GEF ALS2 homo-oligomerization also the of and the loss of oligomerization the endosomal we that the ALS2 the domain one of the the endosomal and endosome whereas the localized onto compartments and the These results that homo-oligomerization is one of the fundamental molecular features for the ALS2 function in vivo. that oligomer is for the endosomal and function of ALS2, the ALS2 also in the cells. the ALS2 as Rab5GEF we the that the loss of Rab5GEF activity oligomerization in the of the protein Recently, several the and function of the ALS2 protein have been J. Full Text Full Text PDF PubMed Scopus Google Scholar, K. C. Eymard-Pierre E. Bertini E. Boespflug-Tanguy O. D.W. S. A. 2003; PubMed Scopus Google Scholar). We have demonstrated the of and domains within the ALS2 A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar). The N-terminal to of ALS2 onto and/or in non-neuronal cells. the domains the endosomal of ALS2 the the C-terminal endosome fusions in vivo. is the Rab5GEF activity A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar), to function as an to the the ALS2 the region which the oligomerization and the endosome indicating that the of domains by the region crucial for the endosome in the cells A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar). J. Full Text Full Text PDF PubMed Scopus Google Scholar) also that and domains in the ALS2 with also that the domain with and that of ALS2 with in cells in an in the of form of the that we and have to the ALS2-associated GEF activity A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar, J. Full Text Full Text PDF PubMed Scopus Google Scholar). These results that ALS2 the through the and is the ALS2-mediated to the endosome the K. C. Eymard-Pierre E. Bertini E. Boespflug-Tanguy O. D.W. S. A. 2003; PubMed Scopus Google Scholar) have a that endosomal of ALS2 is through the Recently, we found that of expressed ALS2 and its to in of cells A. S. Okada T. H. R. H. Showguchi-Miyata J. Yanagisawa Y. E. E. M. Osuga H. T. S. Ikeda J.-E. Hum. Genet. 2003; PubMed Scopus Google Scholar). of cells and the of the ALS2 domains the of ALS2 the in the physiological to the that and function of ALS2 by the which a physiological we demonstrated the molecular for the homophilic oligomerization to associated with Rab5GEF activity. the Rab5GEF family ALS2 is only to its to form homophilic K. J. H. K. H. T. J. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar) that as a of of to of is essential for its Rab5GEF activity the one of the characterized been shown to with H. R. M. H. V. M. K. M. M. Full Text Full Text PDF PubMed Scopus Google Scholar, H. G. O. M. Full Text PDF PubMed Scopus Google Scholar, V. O. M. K. R. M. 1996; PubMed Scopus Google Scholar). This enhanced the Rab5GEF activity and was for the endosome fusions R. M. V. A. M. 2001; PubMed Scopus Google Scholar). These that the function as a protein in of several E. J. 2001; PubMed Google Scholar, S. D. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), Dbl K. F. Y. 2001; PubMed Scopus Google Scholar), PubMed Scopus Google Scholar), PubMed Scopus Google Scholar), J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, H. A. Y. H. Y. PubMed Scopus Google Scholar), H. A. Y. H. Y. PubMed Scopus Google Scholar), and H. A. Y. H. Y. PubMed Scopus Google Scholar), have been shown to of oligomerization the in GEF activity of Dbl K. F. Y. 2001; PubMed Scopus Google Scholar) and function in S. D. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). the of and of the C-terminal that for oligomerization the in vitro GEF in the of in J. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, H. A. Y. H. Y. PubMed Scopus Google Scholar). Taken together, these that oligomerization an important molecular feature in the the small which by of with fundamental in physiological independent homozygous ALS2 mutations in three distinct recessive motor neuron diseases, ALS2, and have been these mutations the of the to the ALS2 a feature to these mutations is the loss of of to the loss of the ALS2-associated Rab5GEF activity the for these we identified a that the by This is to ALS2 protein which is and the the of is and its is also is that ALS2 the function of ALS2 by important ALS2 in in the of endosome we that the ALS2 oligomerization is crucial for the ALS2-mediated of endosome These an important to the ALS2 endosomal to ALS2 a also that ALS2 the neuronal cells by K. Y. T. S. M. J. Full Text Full Text PDF PubMed Scopus Google Scholar), the function for the function for ALS2 the of a number of recessive motor neuron by loss of in the ALS2 We to the of for and

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