Bipartite determinants mediate an evolutionarily conserved interaction between Cdc48 and the 20S peptidase
Author(s)Sauer, Robert T.; Barthelme, Dominik
DownloadBarthelme-2013-Bipartite determinants mediate an evolutionarily conserved interaction between Cdc48 and the 20S peptidase.pdf (736.5Kb)
MetadataShow full item record
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[subscript 1–6]–20S interactions in the 26S proteasome. Current dogma holds that the Rpt[subscript 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.
DepartmentMassachusetts Institute of Technology. Department of Biology
Proceedings of the National Academy of Sciences
National Academy of Sciences (U.S.)
Barthelme, D., and R. T. Sauer. “Bipartite determinants mediate an evolutionarily conserved interaction between Cdc48 and the 20S peptidase.” Proceedings of the National Academy of Sciences 110, no. 9 (February 26, 2013): 3327-3332.
Final published version