p97/valosin‐containing protein (VCP) is highly modulated by phosphorylation and acetylation

Mori-Konya, Chiho; Kato, Naruyoshi; Maeda, Ryota; Yasuda, Kouji; Higashimae, Naoki; Noguchi, Masatoshi; Koike, Masayuki; Kimura, Yoko; Ohizumi, Hiroshi; Hori, Seiji; Kakizuka, Akira

doi:10.1111/j.1365-2443.2009.01286.x

Cited by 47 publications

(45 citation statements)

References 41 publications

(83 reference statements)

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“…These sequential modifications were not observed in VCP purified from cells expressing normal lengths of polyglutamines. The same sequential modifications were observed, although less frequently, in purified FLAG-VCP from MG132-treated cells (34). In the absence of MG132 treatment, these sequential modifications were not detected by LC/MS/MS analysis.…”

Section: Resultssupporting

confidence: 52%

“…VCP Modification and Atrophic Phenotypes-We have previously shown that VCP is highly modified by phosphorylation and acetylation (34). We thus purified FLAG-VCP from HEK293T cells expressing expanded polyglutamine tracts, analyzed it by LC/MS/MS, and found that three sequential amino acids, Ser-612, Thr-613, and Lys-614, were modified simultaneously by phosphorylation, phosphorylation, and acetylation, respectively (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Next, the samples were excised from the gels and were treated with trypsin. The tryptic-digested peptides were analyzed by LC/MS/MS (Waters, 2795 separation module/Thermo Finnigan, LCQ Deca XP plus) (34).…”

Section: Methodsmentioning

confidence: 99%

“…In addition, by genetic screening using Drosophila models of polyglutamine disease, we identified ter94, the Drosophila homolog of VCP, as a genetic modifier of eye degeneration phenotypes induced by expanded polyglutamine tracts (30). VCP has also been shown to be highly modified by S-thiolation, phosphorylation, and acetylation (31)(32)(33)(34).…”

mentioning

confidence: 99%

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Valosin-containing Protein (VCP) in Novel Feedback Machinery between Abnormal Protein Accumulation and Transcriptional Suppression

Koike

Fukushi

Ichinohe

et al. 2010

Journal of Biological Chemistry

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Abnormal protein accumulation is often observed in human neurodegenerative disorders such as polyglutamine diseases and Parkinson disease. Genetic and biochemical analyses indicate that valosin-containing protein (VCP) is a crucial molecule in the pathogenesis of human neurodegenerative disorders. We report here that VCP was specifically modified in neuronal cells with abnormal protein accumulation; this modification caused the translocation of VCP into the nucleus. Modification-mimic forms of VCP induced transcriptional suppression with deacetylation of core histones, leading to cell atrophy and the decrease of de novo protein synthesis. Preventing VCP nuclear translocation in polyglutamine-expressing neuronal cells and Drosophila eyes mitigated neurite retraction and eye degenerations, respectively, concomitant with the recovery of core histone acetylation. This represents a novel feedback mechanism that regulates abnormal protein levels in the cytoplasm during physiological processes, as well as in pathological conditions such as abnormal protein accumulation in neurodegenerations.

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Section: Resultssupporting

confidence: 52%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Valosin-containing Protein (VCP) in Novel Feedback Machinery between Abnormal Protein Accumulation and Transcriptional Suppression

Koike

Fukushi

Ichinohe

et al. 2010

Journal of Biological Chemistry

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“…This residue had already been reported as a site of acetylation [192], but given the modest size discrepancy between lysine acetylation and trimethylation, it is possible that assignment of acetylation to this residue was rather the result of misannotation. The target lysine lies within VCP's first ATPase domain, and it was shown that methylation of this residue results in abrogation of the individual domain's ATPase activity in vitro.…”

Section: Methylationmentioning

confidence: 93%

Regulation of molecular chaperones through post-translational modifications: Decrypting the chaperone code

Cloutier

Coulombe

2013

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Molecular chaperones and their associated cofactors form a group of highly specialized proteins that orchestrate the folding and unfolding of other proteins and the assembly and disassembly of protein complexes. Chaperones are found in all cell types and organisms, and their activity must be tightly regulated to maintain normal cell function. Indeed, deregulation of protein folding and protein complex assembly is the cause of various human diseases. Here, we present the results of an extensive review of the literature revealing that the post-translational modification (PTM) of chaperones has been selected during evolution as an efficient mean to regulate the activity and specificity of these key proteins. Because the addition and reciprocal removal of chemical groups can be triggered very rapidly, this mechanism provides an efficient switch to precisely regulate the activity of chaperones on specific substrates. The large number of PTMs detected in chaperones suggests that a combinatory code is at play to regulate function, activity, localization, and substrate specificity for this group of biologically important proteins. This review surveys the core information currently available as a starting point toward the more ambitious endeavor of deciphering the "chaperone code".

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Millisecond dynamic of SARS‐CoV‐2 spike and its interaction with ACE2 receptor and small extracellular vesicles

Lim

Nishide

Yoshida

et al. 2021

J of Extracellular Vesicle

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SARS‐CoV‐2 spike protein (S) binds to human angiotensin‐converting enzyme 2 (hACE2), allowing virus to dock on cell membrane follow by viral entry. Here, we use high‐speed atomic force microscopy (HS‐AFM) for real‐time visualization of S, and its interaction with hACE2 and small extracellular vesicles (sEVs). Results show conformational heterogeneity of S, flexibility of S stalk and receptor‐binding domain (RBD), and pH/temperature‐induced conformational change of S. S in an S‐ACE2 complex appears as an all‐RBD up conformation. The complex acquires a distinct topology upon acidification. S and S2 subunit demonstrate different membrane docking mechanisms on sEVs. S‐hACE2 interaction facilitates S to dock on sEVs, implying the feasibility of ACE2‐expressing sEVs for viral neutralization. In contrary, S2 subunit docks on lipid layer and enters sEV using its fusion peptide, mimicking the viral entry scenario. Altogether, our study provides a platform that is suitable for real‐time visualization of various entry inhibitors, neutralizing antibodies, and sEV‐based decoy in blocking viral entry. Teaser: Comprehensive observation of SARS‐CoV‐2 spike and its interaction with receptor ACE2 and sEV‐based decoy in real time using HS‐AFM.

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p97/valosin‐containing protein (VCP) is highly modulated by phosphorylation and acetylation

Cited by 47 publications

References 41 publications

Valosin-containing Protein (VCP) in Novel Feedback Machinery between Abnormal Protein Accumulation and Transcriptional Suppression

Valosin-containing Protein (VCP) in Novel Feedback Machinery between Abnormal Protein Accumulation and Transcriptional Suppression

Regulation of molecular chaperones through post-translational modifications: Decrypting the chaperone code

Millisecond dynamic of SARS‐CoV‐2 spike and its interaction with ACE2 receptor and small extracellular vesicles

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