title: Human VAPA and the yeast VAP Scs2p with an altered proline distribution can phenocopy amyotrophic lateral sclerosis-associated VAPB(P56S).
abstract: A human isoform of the vesicle-associated membrane protein-associated proteins (VAPs), VAPB, causes amyotrophic lateral sclerosis eight due to the missense mutation of Pro-56, whereas human VAPA and the yeast VAP Scs2p proteins are not significantly affected by similar mutations. We have found that VAPA and Scs2p have three prolines present in a conserved region however VAPB has only two prolines in this region. Consequently, this mutation in VAPB (VAPB(P56S)) leaves a single proline in this region whereas other VAPs can retain two proline residues even if the proline equivalent to the Pro-56 is substituted. When Scs2p and VAPA were mutated to be equivalent to VAPB(P56S) in terms of the distribution of proline residues in this region, Scs2p became inactive and aggregated, and VAPA localize to membranous aggregates indistinguishable from those induced by VAPB(P56S). This suggests that the appropriate distribution of three conserved prolines, not the existence of a particular proline, confers VAPA and Scs2p resistance to the Pro-56 mutation and, therefore, is critical for VAP activities.
authors.affiliation: Department of Biological Science and Environment, Graduate School of Humanities and Sciences, Nara Women's University, Nara 630-8506, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Nakamichi
authors.forename: Kumiko
authors.initials: K
authors.lastname: Yamanaka
authors.forename: Mai
authors.initials: M
authors.lastname: Suzuki
authors.forename: Toshio
authors.initials: T
authors.lastname: Watanabe
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kagiwada
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D017124:Conserved Sequence; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D011392:Proline / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D029701:Saccharomyces cerevisiae Proteins; C501314:Scs2 protein, S cerevisiae; C114051:VAPA protein, human; C496748:VAPB protein, human; D033921:Vesicular Transport Proteins; D011392:Proline