p97/valosin-containing protein (VCP) is highly modulated by phosphorylation and acetylation
p97/valosin-containing protein (VCP) is highly modulated by phosphorylation and acetylation
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DOI：
10.1111/j.1365-2443.2009.01286.x
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发表时间：
2009-04-01
期刊：
影响因子：
2.1
通讯作者：
Kakizuka, Akira
中科院分区：
文献类型：
--
作者：
Mori-Konya, Chiho;Kato, Naruyoshi;Kakizuka, Akira
P97/Valosin-Holding Protein(VCP)是AAA家族蛋白中的一员，通过其ATPase活性在细胞中发挥多种重要作用。但其ATPase活性的调节机制大多尚不清楚。我们在这里报道，VCP通过乙酰化和磷酸化在整个蛋白质中高度修饰。除了先前发现的6个磷酸化位点外，我们还确定了至少14个丝氨酸、14个苏氨酸、6个酪氨酸和22个赖氨酸作为潜在的修饰位点。有趣的是，这些位点包括Lys(251)和Lys(524)，它们分别对D1和D2结构域的Walker A基序中的ATP结合非常关键。值得注意的是，N-末端有16个位点，D2α结构域有16个位点聚集(从Pro(646)到Gly(765))。事实上，赖氨酸(696)和苏氨酸(761)的氨基酸取代对VCP ATPase活性有深远的影响。根据这些结果，我们认为D2α结构域可能作为VCP ATPase调节域或“VAR结构域”。VCP的修饰，包括VAR结构域的修饰，可能在不同的细胞条件下，如在细胞周期和蛋白质异常积累的情况下，支持对VCP的适应性和多种功能。
p97/valosin-containing protein (VCP) is a member of the AAA family proteins, which plays various important roles in cells by using its ATPase activity. But mechanism of regulating its ATPase activity is mostly unknown. We report here that VCP is highly modified throughout the protein via acetylation and phosphorylation. In addition to six previously identified phosphorylation sites, we identified at least 14 serines, 14 threonines, 6 tyrosines and 22 lysines as potential modification sites. Interestingly, these sites included Lys(251) and Lys(524), which are very critical for the ATP binding in Walker A motif of D1 and D2 domains, respectively. It is notable that 16 sites are in the N-terminal region and 16 sites are clustered in D2 alpha domain (from Pro(646) to Gly(765)). Indeed, amino acid substitution of Lys(696) and Thr(761) profoundly affect VCP ATPase activities. From these results, we propose that D2 alpha domain acts as a VCP ATPase Regulatory domain or "VAR domain". VCP modifications including those in this VAR domain may endorse adaptive and multiple functions to VCP in different cell conditions such as in the cell cycle and with abnormal protein accumulation.