The ubiquitin-proteasome (Ub-Pr) mediated degradation pathway has been shown to regulate many important cellular processes. The pathway consists of two sequential steps: the target protein is first conjugated with multiple ubiquitin molecules, then transferred to the 26S proteasome, unfolded, and degraded. Although much is known about how the substrate is conjugated with multi-ubiquitin chains, it is unclear how such substrate is targeted and delivered to the proteasome. We previously identified Valosin-containing protein (VCP), a highly conserved ATPase, physically associated with both the ubiquitinated substrates and the purified 26S proteasome. Based on our further work showing VCP as a ubiquitin chain-binding factor, we propose a model whereby VCP acts as a molecular chaperone that disassembles protein complex, and targets the ubiquitinated substrate to the proteasome for degradation. Since Ub-Pr pathway regulates a variety of cell functions, this link immediately suggests that, through the pathway, VCP plays a critical role in regulating these important activities. These activities include cell growth, apoptosis, immune and stress responses, and ER-associated degradation, etc., all bearing high impact on health and disease issues. Recently, we further carried out structure-functional analysis in VCP, and identified D1 as the major oligomerization domain, and D2 as the major contributor to the enzyme activity. Moreover, we identified a novel heat-inducible ATPase activity in VCP, which is mediated by the D1 domain. These studies further provide a molecular mechanism underlying the involvement of VCP in heat shock and stress responses.
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|Wang, Qing; Song, Changcheng; Yang, Xiaoyi et al. (2003) D1 ring is stable and nucleotide-independent, whereas D2 ring undergoes major conformational changes during the ATPase cycle of p97-VCP. J Biol Chem 278:32784-93|
|Wang, Qing; Song, Changcheng; Li, Chou-Chi H (2003) Hexamerization of p97-VCP is promoted by ATP binding to the D1 domain and required for ATPase and biological activities. Biochem Biophys Res Commun 300:253-60|
|Song, Changcheng; Wang, Qing; Li, Chou-Chi H (2003) ATPase activity of p97-valosin-containing protein (VCP). D2 mediates the major enzyme activity, and D1 contributes to the heat-induced activity. J Biol Chem 278:3648-55|