RGD Reference Report - Function of the p97-Ufd1-Npl4 complex in retrotranslocation from the ER to the cytosol: dual recognition of nonubiquitinated polypeptide segments and polyubiquitin chains. - Rat Genome Database

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Function of the p97-Ufd1-Npl4 complex in retrotranslocation from the ER to the cytosol: dual recognition of nonubiquitinated polypeptide segments and polyubiquitin chains.

Authors: Ye, Y  Meyer, HH  Rapoport, TA 
Citation: Ye Y, etal., J Cell Biol. 2003 Jul 7;162(1):71-84.
RGD ID: 10047330
Pubmed: PMID:12847084   (View Abstract at PubMed)
PMCID: PMC2172719   (View Article at PubMed Central)
DOI: DOI:10.1083/jcb.200302169   (Journal Full-text)

A member of the family of ATPases associated with diverse cellular activities, called p97 in mammals and Cdc48 in yeast, associates with the cofactor Ufd1-Npl4 to move polyubiquitinated polypeptides from the endoplasmic reticulum (ER) membrane into the cytosol for their subsequent degradation by the proteasome. Here, we have studied the mechanism by which the p97-Ufd1-Npl4 complex functions in this retrotranslocation pathway. Substrate binding occurs when the first ATPase domain of p97 (D1 domain) is in its nucleotide-bound state, an interaction that also requires an association of p97 with the membrane through its NH2-terminal domain. The two ATPase domains (D1 and D2) of p97 appear to alternate in ATP hydrolysis, which is essential for the movement of polypeptides from the ER membrane into the cytosol. The ATPase itself can interact with nonmodified polypeptide substrates as they emerge from the ER membrane. Polyubiquitin chains linked by lysine 48 are recognized in a synergistic manner by both p97 and an evolutionarily conserved ubiquitin-binding site at the NH2 terminus of Ufd1. We propose a dual recognition model in which the ATPase complex binds both a nonmodified segment of the substrate and the attached polyubiquitin chain; polyubiquitin binding may activate the ATPase p97 to pull the polypeptide substrate out of the membrane.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Nploc4RatERAD pathway involved_inIDA PMID:12847084ComplexPortal 
Ufd1RatERAD pathway involved_inIDA PMID:12847084ComplexPortal 
VcpRatERAD pathway involved_inIDA PMID:12847084ComplexPortal 
Nploc4Ratretrograde protein transport, ER to cytosol involved_inEXP PMID:12847084ComplexPortal 
Ufd1Ratretrograde protein transport, ER to cytosol involved_inEXP PMID:12847084ComplexPortal 
VcpRatretrograde protein transport, ER to cytosol involved_inEXP PMID:12847084ComplexPortal 

Cellular Component

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Nploc4RatVCP-NPL4-UFD1 AAA ATPase complex part_ofNAS PMID:12847084ParkinsonsUK-UCL 
Ufd1RatVCP-NPL4-UFD1 AAA ATPase complex part_ofIPIUniProtKB:Q01853PMID:12847084ParkinsonsUK-UCL 
Nsfl1cRatVCP-NSFL1C complex part_ofIPIUniProtKB:Q01853PMID:12847084ParkinsonsUK-UCL 

Molecular Function

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Ufd1RatATPase binding enablesIPIUniProtKB:Q01853PMID:12847084ParkinsonsUK-UCL 
Nploc4RatK48-linked polyubiquitin modification-dependent protein binding contributes_toIDA PMID:12847084ParkinsonsUK-UCL 
Nploc4RatK63-linked polyubiquitin modification-dependent protein binding contributes_toIDA PMID:12847084ParkinsonsUK-UCL 
Nsfl1cRatprotein binding enablesIPIUniProtKB:Q01853PMID:12847084ParkinsonsUK-UCL 

Objects Annotated

Genes (Rattus norvegicus)
Nploc4  (NPL4 homolog, ubiquitin recognition factor)
Nsfl1c  (NSFL1 cofactor)
Ufd1  (ubiquitin recognition factor in ER associated degradation 1)
Vcp  (valosin-containing protein)


Additional Information