Enzymes as chaperones and chaperones as enzymes

Abstract

Chaperones and foldases are two groups of accessory proteins which assist maturation of nascent peptides into functional proteins in cells. Protein disulfide isomerase, a foldase, and ATP-dependent proteases, responsible for degradation of misfolded proteins in cells, both have intrinsic chaperone activities. Trigger factor and DnaJ, well known Escherichia coli chaperones, show peptidyl prolyl isomerase and protein disulfide isomerase activities respectively. It is suggested that the combination of chaperone and enzyme activities in one molecule is the result of evolution to increase molecular efficiency.z 1998 Federation of European Biochemical Societies.Key words: Foldase; Chaperone; Protein disul¢de isomerase ; Trigger factor; ATP-dependent protease; Protein folding From spontaneous to assisted foldingIt is now widely accepted that a large number of proteins do not fold and assemble spontaneously in vivo to form the biologically active molecules but require the help of other proteins. This results in a conceptional transition for protein folding: from the classical`self-assembly' to the new`assisted assembly' principle [1]. Most in vitro experiments employed conditions considerably di¡erent from the in vivo situation of high protein concentrations with a high risk of aggregation [2] and relatively high temperature for warm-blooded animals. The evolution of higher organisms must create a mechanism to overcome problems resulting from the crowded protein solution and the elevated temperature.Two groups of proteins have been found to function as accessory proteins for folding: molecular chaperones and foldases which catalyze the necessary covalent reactions directly involved in protein folding [3]. Only two foldases, protein disul¢de isomerase (PDI) and peptidyl prolyl cis-trans isomerase (PPI), have so far been characterized as foldases. Based on the de¢nition of molecular chaperones as proteins assisting correct folding without covalent changes the foldases were therefore excluded as chaperones [1]. Chaperone activity of protein disul¢de isomerasePDI, a multifunctional protein present in the endoplasmic reticulum at high concentration [4], is remarkable in its capacity of non-speci¢c peptide binding, an important feature for a protein to be a molecular chaperone. In addition, for PDI to promote the joining of thiol groups distantly situated in the peptide sequence to form correct disul¢des the peptide chain has to be folded at least to some extent to bring the thiol groups together. The spontaneous folding of the peptide chain and the oxidation of thiol groups in vitro are often slow processes and the PDI-catalyzed folding does not need the presence of other chaperones. We therefore put forward the hypothesis that PDI is both an enzyme and a molecular chaperone [5]. Many in vitro and in vivo data have now accumulated to support the hypothesis that in addition to its isomerase activity in the catalysis of native disul¢de formation PDI does have intrinsic activity as a chaperone [6^13].The folding of a p...

The alphabet of intrinsic disorder

“…Therefore, classes of cellular enzymes, so-called peptidyl-prolyl isomerases (PPIases), specifically enhance proline cis/trans isomerization without affecting their thermodynamic equilibrium states 181 . PPIases are evolutionarily conserved and often characterized as foldases, or annotated as catalytic structural chaperones 182 . Due to their inherent differences in stereochemistry, proline c is / trans isomers can also define different functional states of proteins 183 .…”

FK506-binding protein of the hyperthermophilic archaeum, Thermococcus sp. KS-1, a cold-shock-inducible peptidyl-prolyl cis–trans isomerase with activities to trap and refold denatured proteins

“…Peptidyl-prolyl cis-trans isomerase (PPIase), protein disulphide isomerase and various molecular chaperones have been identified as mediators of protein folding and assembly in i o [1]. PPIases are classified into three distinct families according to their sensitivity to inhibitors [2][3][4].…”

Recent advances in biomolecular process intensification

“…disulfide and proline isomerases). Chaperones recognise the hydrophobic patches of nascent polypeptides and form transient complexes with the peptides, thereby protecting them from misfolding (Wang and Tsou, 1998). Secondly, competing folding configurations implicated with longer stretches of full-length polypeptides, often observed during in vitro refolding, are rarely encountered within cells since transcription and translation are coupled in bacteria and co-translational domain folding of larger proteins is possible before full-length proteins emerge (Champe and Harvey, 1994;Netzer and Hartl, 1997).…”