Document Detail

Bipartite determinants mediate an evolutionarily conserved interaction between Cdc48 and the 20S peptidase.
MedLine Citation:
PMID:  23401548     Owner:  NLM     Status:  MEDLINE    
Proteasomes are essential and ubiquitous ATP-dependent proteases that function in eukarya, archaea, and some bacteria. These destructive but critically important proteolytic machines use a 20S core peptidase and a hexameric ATPase associated with a variety of cellular activities (AAA+) unfolding ring that unfolds and spools substrates into the peptidase chamber. In archaea, 20S can function with the AAA+ Cdc48 or proteasome-activating nucleotidase (PAN) unfoldases. Both interactions are stabilized by C-terminal tripeptides in AAA+ subunits that dock into pockets on the 20S periphery. Here, we provide evidence that archaeal Cdc48 also uses a distinct set of near-axial interactions to bind 20S and propose that similar dual determinants mediate PAN-20S interactions and Rpt(1-6)-20S interactions in the 26S proteasome. Current dogma holds that the Rpt(1-6) unfolding ring of the 19S regulatory particle is the only AAA+ partner of eukaryotic 20S. By contrast, we show that mammalian Cdc48, a key player in cell-cycle regulation, membrane fusion, and endoplasmic-reticulum-associated degradation, activates mammalian 20S and find that a mouse Cdc48 variant supports protein degradation in combination with 20S. Our results suggest that eukaryotic Cdc48 orthologs function directly with 20S to maintain intracellular protein quality control.
Dominik Barthelme; Robert T Sauer
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-02-11
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  110     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-27     Completed Date:  2013-05-02     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3327-32     Citation Subset:  IM    
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MeSH Terms
Adenosine Triphosphatases / chemistry,  metabolism*
Amino Acid Motifs
Amino Acid Sequence
Archaeal Proteins / chemistry,  metabolism
Cell Cycle Proteins / chemistry,  metabolism*
Evolution, Molecular*
Models, Biological
Molecular Sequence Data
Mutant Proteins / metabolism
Proteasome Endopeptidase Complex / chemistry,  metabolism*
Protein Binding
Protein Structure, Secondary
Saccharomyces cerevisiae / enzymology
Substrate Specificity
Thermoplasma / metabolism
Grant Support
Reg. No./Substance:
0/Archaeal Proteins; 0/Cell Cycle Proteins; 0/Mutant Proteins; EC Endopeptidase Complex; EC 3.6.1.-/Adenosine Triphosphatases; EC 3.6.1.-/CDC48 protein; EC 3.6.4.-/PAN enzyme

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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