Department of Biological Science and Environment, Graduate School of Humanities and Sciences, Nara Women's University, Nara 630-8506, Japan.
Biochem Biophys Res Commun. 2011 Jan 14;404(2):605-9. doi: 10.1016/j.bbrc.2010.12.011. Epub 2010 Dec 7.
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.
一种囊泡相关膜蛋白相关蛋白（VAPs）的人类同工型 VAPB，由于脯氨酸 56 的错义突变，导致肌萎缩侧索硬化症 8 型，而人类 VAPA 和酵母 VAP Scs2p 蛋白则没有受到类似突变的显著影响。我们发现 VAPA 和 Scs2p 在保守区域中存在三个脯氨酸，而 VAPB 在此区域中只有两个脯氨酸。因此，VAPB 中的这种突变（VAPB[P56S]）在该区域中只剩下一个脯氨酸，而其他 VAP 即使脯氨酸相当于 Pro-56 被取代，也可以保留两个脯氨酸残基。当 Scs2p 和 VAPA 突变为在该区域的脯氨酸残基分布等效于 VAPB[P56S]时，Scs2p 失活并聚集，而 VAPA 定位于与 VAPB[P56S]诱导的膜状聚集体无法区分的膜状聚集体中。这表明，三个保守脯氨酸的适当分布，而不是特定脯氨酸的存在，赋予了 VAPA 和 Scs2p 对 Pro-56 突变的抗性，因此对于 VAP 活性至关重要。
