title: Biochemical characterization of missense mutations in the Arf/Arl-family small GTPase Arl6 causing Bardet-Biedl syndrome.
abstract: Bardet-Biedl syndrome (BBS) is a pleiotropically genetic disorder, whose etiology is linked to cilia. Mutations in the Arf/Arl-family GTPase Arl6 have been recently shown to be responsible for BBS type 3. Here we show that BBS mutations alter the guanine nucleotide-binding properties of Arl6. Specifically, substitution of 31st Threonine to Arginine selectively abrogates the GTP-binding ability of Arl6 without affecting GDP-binding/dissociating properties. Furthermore, all the BBS mutations in Arl6 result in low expression of the mutant proteins, which can be restored by the inhibition of the proteasome. These findings implicate that Arl6 mutants are destabilized and eliminated by the proteasome in cells, probably due to the altered nucleotide-binding properties.
authors.affiliation: Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hori
authors.forename: Nami
authors.initials: N
authors.lastname: Ueda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kajiho
authors.forename: Shin
authors.initials: S
authors.lastname: Muraoka
authors.forename: Fumi
authors.initials: F
authors.lastname: Shima
authors.forename: Tohru
authors.initials: T
authors.lastname: Kataoka
authors.forename: Kenji
authors.initials: K
authors.lastname: Kontani
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Katada
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D020788:Bardet-Biedl Syndrome / Q000201:enzymology* / Q000235:genetics; D002460:Cell Line; D004285:Dogs; D004795:Enzyme Stability / Q000235:genetics; D006147:Guanine / Q000378:metabolism; D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism
chemical_list: D006147:Guanine; D046988:Proteasome Endopeptidase Complex; C491435:ARL6 protein, human; D020727:ADP-Ribosylation Factors; D020559:Monomeric GTP-Binding Proteins