title: Oxidative protein folding: from thiol-disulfide exchange reactions to the redox poise of the endoplasmic reticulum.
abstract: This review examines oxidative protein folding within the mammalian endoplasmic reticulum (ER) from an enzymological perspective. In protein disulfide isomerase-first (PDI-first) pathways of oxidative protein folding, PDI is the immediate oxidant of reduced client proteins and then addresses disulfide mispairings in a second isomerization phase. In PDI-second pathways the initial oxidation is PDI-independent. Evidence for the rapid reduction of PDI by reduced glutathione is presented in the context of PDI-first pathways. Strategies and challenges are discussed for determination of the concentrations of reduced and oxidized glutathione and of the ratios of PDI(red):PDI(ox). The preponderance of evidence suggests that the mammalian ER is more reducing than first envisaged. The average redox state of major PDI-family members is largely to almost totally reduced. These observations are consistent with model studies showing that oxidative protein folding proceeds most efficiently at a reducing redox poise consistent with a stoichiometric insertion of disulfides into client proteins. After a discussion of the use of natively encoded fluorescent probes to report the glutathione redox poise of the ER, this review concludes with an elaboration of a complementary strategy to discontinuously survey the redox state of as many redox-active disulfides as can be identified by ratiometric LC-MS-MS methods. Consortia of oxidoreductases that are in redox equilibrium can then be identified and compared to the glutathione redox poise of the ER to gain a more detailed understanding of the factors that influence oxidative protein folding within the secretory compartment.
authors.affiliation: Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA.
authors.forename: Devin A
authors.initials: DA
authors.lastname: Hudson
authors.affiliation: Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA.
authors.forename: Shawn A
authors.initials: SA
authors.lastname: Gannon
authors.affiliation: Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA. Electronic address: cthorpe@udel.edu.
authors.forename: Colin
authors.initials: C
authors.lastname: Thorpe
mesh_terms: D000818:Animals; D004220:Disulfides / Q000737:chemistry* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D005057:Eukaryotic Cells / Q000166:cytology / Q000201:enzymology; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism; D019803:Glutathione Disulfide / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D010084:Oxidation-Reduction; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000737:chemistry* / Q000378:metabolism; D019704:Protein Disulfide-Isomerases / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding; D015800:Protozoan Proteins / Q000737:chemistry* / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000378:metabolism; D014346:Trypanosoma brucei brucei / Q000166:cytology / Q000201:enzymology
chemical_list: D004220:Disulfides; D015800:Protozoan Proteins; D013438:Sulfhydryl Compounds; D050862:Oxidoreductases Acting on Sulfur Group Donors; C548687:quiescin sulfhydryl oxidase, Trypanosoma brucei; D019704:Protein Disulfide-Isomerases; D005978:Glutathione; D019803:Glutathione Disulfide
keywords: Disulfide exchange; Endoplasmic reticulum; Ero1; Glutathione; Oxidative protein folding; Peroxiredoxin; Protein disulfide isomerase; Quiescin sulfhydryl oxidase; Ratiometric mass spectrometry; Redox potential
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