title: p97/valosin-containing protein (VCP) is highly modulated by phosphorylation and acetylation.
abstract: 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 Lys251 and Lys524, 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 D2alpha domain (from Pro646 to Gly765). Indeed, amino acid substitution of Lys696 and Thr761 profoundly affect VCP ATPase activities. From these results, we propose that D2alpha 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.
authors.affiliation: The Laboratory of Functional Biology, Kyoto University Graduate School of Biostudies and Solution Oriented Research for Science and Technology (JST), Kyoto 606-8501, Japan.
authors.forename: Chiho
authors.initials: C
authors.lastname: Mori-Konya
authors.forename: Naruyoshi
authors.initials: N
authors.lastname: Kato
authors.forename: Ryota
authors.initials: R
authors.lastname: Maeda
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Yasuda
authors.forename: Naoki
authors.initials: N
authors.lastname: Higashimae
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Noguchi
authors.forename: Masaaki
authors.initials: M
authors.lastname: Koike
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kimura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohizumi
authors.forename: Seiji
authors.initials: S
authors.lastname: Hori
authors.forename: Akira
authors.initials: A
authors.lastname: Kakizuka