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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Adenosine Triphosphatases / metabolism*
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Carrier Proteins / chemistry
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Carrier Proteins / metabolism*
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Cell Line
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Cullin Proteins / metabolism
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DNA-Binding Proteins / metabolism
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Humans
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Models, Molecular
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NEDD8 Protein
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Nuclear Proteins / metabolism*
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Polycomb Repressive Complex 1
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Protein Interaction Domains and Motifs
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Protein Interaction Maps
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Ubiquitin / metabolism
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitins / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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CUL2 protein, human
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CUL4A protein, human
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Carrier Proteins
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Cullin Proteins
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DNA-Binding Proteins
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NEDD8 Protein
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NEDD8 protein, human
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Nuclear Proteins
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UBXN7 protein, human
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Ubiquitin
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Ubiquitins
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Polycomb Repressive Complex 1
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RING1 protein, human
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Ubiquitin-Protein Ligases
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Adenosine Triphosphatases
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p97 ATPase