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

den Besten, Willem and Verma, Rati and Kleiger, Gary and Oania, Robert S. and Deshaies, Raymond J. (2012) NEDD8 links cullin-RING ubiquitin ligase function to the p97 pathway. Nature Structural & Molecular Biology, 19 (5). pp. 511-516. ISSN 1545-9985. PMCID PMC3348432.

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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.

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Kleiger, Gary0000-0003-3924-1680
Deshaies, Raymond J.0000-0002-3671-9354
Additional Information:© 2012 Nature Publishing Group, a division of Macmillan Publishers Limited. Received 6 September 2011; accepted 18 February 2012; published online 1 April 2012. We thank M. Rome for providing Lys48-linked polyubiquitin chains, N. Pierce for purified SCFCdc4, T. Hagen (National University of Singapore) and E. Emberley for cullin expression constructs, and D. Duda and B. Schulman (St. Jude Children’s Research Hospital) for providing purified recombinant CUL2, CUL3, CUL4a, CUL1ΔWHB and NCE2 proteins. We are grateful to S. Lewis for help with the Rosetta Dock server, Millennium Pharmaceuticals for MLN4924 and NEDD8 antibody, and the members of the Deshaies laboratory for helpful discussion during the course of this work. This work was supported by the Howard Hughes Medical Institute (HHMI) and a National Institute of Health Ruth Kirschstein Postdoctoral Fellowship (F32 GM088975; W.d.B.). R.J.D. is an HHMI Investigator. Author Contributions: W.d.B. and R.J.D. conceived and designed the experiments; W.d.B. performed most of the experiments, except that G.K. performed the structural modeling in Figure 3a, and R.V. and R.S.O. made the yeast strains and carried out the Rbp1 turnover studies in Figure 5b and c; W.d.B. and R.J.D. wrote the manuscript with editorial input from the other authors.
Funding AgencyGrant Number
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
NIH Ruth Kirschstein Postdoctoral FellowshipF32 GM088975
Issue or Number:5
PubMed Central ID:PMC3348432
Record Number:CaltechAUTHORS:20120601-100510892
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:31767
Deposited By: Jason Perez
Deposited On:01 Jun 2012 19:57
Last Modified:09 Mar 2020 13:18

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