Human VAPA and the yeast VAP Scs2p with an altered proline distribution can phenocopy amyotrophic lateral sclerosis-associated VAPB(P56S) |
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Authors: | Nakamichi Shoko Yamanaka Kumiko Suzuki Mai Watanabe Toshio Kagiwada Satoshi |
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Institution: | aDepartment of Biological Science and Environment, Graduate School of Humanities and Sciences, Nara Women’s University, Nara 630-8506, Japan;bDepartment of Biological Sciences, Faculty of Science, Nara Women’s University, Nara 630-8506, Japan |
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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. |
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Keywords: | Abbreviations: VAP vesicle-associated protein-associated protein MSP major sperm protein FFAT diphenylalanine in an acidic tract ALS amyotrophic lateral sclerosis DAPI 4&prime 6-diamidino-2-phenylindole VCS VAP consensus sequence |
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