Polypeptides emerging from the ribosome must fold into stable three-dimensional structures and maintain that structure throughout their functional lifetimes. Maintaining quality control over protein structure and function depends on molecular chaperones and proteases, both of which can recognize hydrophobic regions exposed on unfolded polypeptides. Molecular chaperones promote proper protein folding and prevent aggregation, and energy-dependent proteases eliminate irreversibly damaged proteins. The kinetics of partitioning between chaperones and proteases determines whether a protein will be destroyed before it folds properly. When both quality control options fail, damaged proteins accumulate as aggregates, a process associated with amyloid diseases.

No abstract

The two major molecular chaperone families that mediate ATP-dependent protein folding and refolding are the heat shock proteins Hsp6Os (GroEL) and Hsp7Os (DnaK). Cip proteins, like chaperones, are highly conserved, present in all organisms, and contain ATP and polypeptide binding sites. We discovered that CipA, the ATPase component of the ATP-dependent ClpAP protease, is a molecular chaperone. CipA performs the ATP-dependent chaperone function of DnaK and DnaJ in the in vitro activation of the plasmid P1 RepA replication initiator protein. RepA is activated by the conversion of dimers to monomers. We show that CipA targets RepA for degradation by ClpP, demonstrating a direct link between the protein unfolding function of chaperones and proteolysis. In another chaperone assay, ClpA protects luciferase from irreversible heat inactivation but is unable to reactivate luciferase.Molecular chaperones interact with other proteins to mediate ATP-dependent protein folding, refolding, assembly, and disassembly of proteins. The Hsp7O chaperone system of Escherichia coli consists of the DnaK, DnaJ, and GrpE heat shock proteins. In vivo these three heat shock proteins function together in many cellular processes, as demonstrated by the observations that mutants in dnaK, dnaJ, and grpE have similar effects on DNA replication of E. coli, plasmids P1 and F and phage A, RNA synthesis, cell division, protein transport, regulation of the heat shock response, protection of enzymes from misfolding or aggregation during heat shock, and degradation of abnormal proteins (reviewed in ref.

-RssB-ClpXP complex forms. The complex degrades S and releases RssB from ClpXP in an ATP-dependent reaction. Our results illuminate an important mechanism for regulated protein turnover in which a unique targeting protein, whose own activity is regulated through specific signaling pathways, catalyzes the delivery of a specific substrate to a specific protease.