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. The multisubunit proteasome has ATPase activity which presumably provides the energy needed for the chaperoning and unfolding of the substrate before its degradation. We previously identified Valosin-containing protein (VCP), a highly conserved ATPase, physically and functionally associated with both the ubiquitinated Ub-Pr substrates and the highly purified proteasome. We hypothesize that VCP is a molecular chaperone that targets the ubiquitinated substrates to the proteasome. VCP and its orthologs, Cdc48p and p97, belong to a highly conserved AAA (ATPases associated with a variety of cellular activities) family. Despite the high sequence and structural similarities preserved among them, VCP and its orthologs are involved in many seemingly unrelated functions, e.g. cell cycle control, T and B cell activation, homotypic membrane fusion, apoptosis, and proteolysis. The paradox suggests that VCP may function in a common mechanism that underlies these activities. Since Ub-Pr pathways have been shown to regulate many substrates that are also involved in these same activities, our hypothesis of VCP being a chaperone in the Ub-Pr pathways would provide the common mechanism explaining the paradox for VCP. We recently demonstrated that VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of stustrates. VCP is an essential component of the Ub-Pr degradation system. Loss of VCP function results in an inhibition of the degradation and an accumulation of multiubiquitinated proteins. Our current and future research focuses on demonstrating the required chaperone role of VCP in Ub-Pr-mediated degradation, and to elucidate the structure-function relationships in VCP.
|Wang, Qing; Song, Changcheng; Li, Chou-Chi H (2004) Molecular perspectives on p97-VCP: progress in understanding its structure and diverse biological functions. J Struct Biol 146:44-57|
|Yang, Yili; Li, Chou-Chi H; Weissman, Allan M (2004) Regulating the p53 system through ubiquitination. Oncogene 23:2096-106|
|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|