Valosin-containing protein is a multi-ubiquitin chain-targeting factor required in ubiquitin-proteasome degradation.

The ubiquitin-proteasome (Ub-Pr) degradation pathway regulates many cellular activities, but how ubiquitinated substrates are targeted to the proteasome is not understood. We have shown previously that valosin-containing protein (VCP) physically and functionally targets the ubiquitinated nuclear factor kappaB inhibitor, IkappaBalpha to the proteasome for degradation. VCP is an abundant and ...
a highly conserved member of the AAA (ATPases associated with a variety of cellular activities) family. Besides acting as a chaperone in membrane fusions, VCP has been shown to have a role in a number of seemingly unrelated cellular activities. Here we report that loss of VCP function results in an inhibition of Ub-Pr-mediated degradation and an accumulation of ubiquitinated proteins. VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of substrates. Furthermore, its N-terminal domain is required in Ub-Pr-mediated degradation. We conclude that VCP is a multi-ubiquitin chain-targeting factor that is required in the degradation of many Ub-Pr pathway substrates, and provide a common mechanism that underlies many of the functions of VCP.
Mesh Terms:
Adenosine Triphosphatases, Binding Sites, Cell Cycle, Cell Cycle Proteins, Cyclin E, Cysteine Endopeptidases, Humans, Molecular Chaperones, Multienzyme Complexes, Mutation, Proteasome Endopeptidase Complex, Protein Structure, Tertiary, Schizosaccharomyces, Tumor Cells, Cultured, Ubiquitins
Nat. Cell Biol.
Date: Aug. 01, 2001
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