title: Chaperone activation by unfolding.
abstract: Conditionally disordered proteins can alternate between highly ordered and less ordered configurations under physiological conditions. Whereas protein function is often associated with the ordered conformation, for some of these conditionally unstructured proteins, the opposite applies: Their activation is associated with their unfolding. An example is the small periplasmic chaperone HdeA, which is critical for the ability of enteric bacterial pathogens like Escherichia coli to survive passage through extremely acidic environments, such as the human stomach. At neutral pH, HdeA is a chaperone-inactive dimer. On a shift to low pH, however, HdeA monomerizes, partially unfolds, and becomes rapidly active in preventing the aggregation of substrate proteins. By mutating two aspartic acid residues predicted to be responsible for the pH-dependent monomerization of HdeA, we have succeeded in isolating an HdeA mutant that is active at neutral pH. We find this HdeA mutant to be substantially destabilized, partially unfolded, and mainly monomeric at near-neutral pH at a concentration at which it prevents aggregation of a substrate protein. These results provide convincing evidence for direct activation of a protein by partial unfolding.
authors.affiliation: Howard Hughes Medical Institute and Department of Chemistry and Biophysics Program, University of Michigan, Ann Arbor, MI 48109-1055, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Foit
authors.forename: Jenny S
authors.initials: JS
authors.lastname: George
authors.forename: Bin W
authors.initials: BW
authors.lastname: Zhang
authors.forename: Charles L
authors.initials: CL
authors.lastname: Brooks
authors.forename: James C A
authors.initials: JC
authors.lastname: Bardwell
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002942:Circular Dichroism; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D016296:Mutagenesis; D019897:Periplasm / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D058767:Protein Unfolding; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D014461:Ultracentrifugation
chemical_list: D029968:Escherichia coli Proteins; D018832:Molecular Chaperones; C084501:hdeA protein, E coli