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NEDD8 links cullin-RING ubiquitin ligase function to the p97 pathway.

ABSTRACT: The AAA+ ATPase p97 and its UBA-UBX cofactors are thought to extract ubiquitinated proteins from membranes or protein complexes as a prelude to their degradation. However, for many cofactors ubiquitinated targets have not yet been identified, leaving their biological function unclear. Previous analysis has linked the p97 pathway to cullin-RING ubiquitin ligases (CRLs); here we demonstrate that the human p97 cofactor UBXD7 mediates the p97-CRL interaction through its conserved ubiquitin-interacting motif (UIM). UBXD7 and its yeast ortholog, Ubx5, associate only with the active, NEDD8- or Rub1-modified form of cullins. Disruption of the Ubx5 UIM results in a loss of CRL binding and consequently impedes degradation of a Cul3 substrate. These results uncover an unexpected and conserved role for NEDD8 in linking CRL ubiquitin ligase function to the p97 pathway.

SUBMITTER: den Besten W

PROVIDER: S-EPMC3348432 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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NEDD8 links cullin-RING ubiquitin ligase function to the p97 pathway.

den Besten Willem W Verma Rati R Kleiger Gary G Oania Robert S RS Deshaies Raymond J RJ

Nature structural & molecular biology 20120401 5

The AAA+ ATPase p97 and its UBA-UBX cofactors are thought to extract ubiquitinated proteins from membranes or protein complexes as a prelude to their degradation. However, for many cofactors ubiquitinated targets have not yet been identified, leaving their biological function unclear. Previous analysis has linked the p97 pathway to cullin-RING ubiquitin ligases (CRLs); here we demonstrate that the human p97 cofactor UBXD7 mediates the p97-CRL interaction through its conserved ubiquitin-interacti ...[more]

PMID: 22466964

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