title: Protein disulphide isomerase family members show distinct substrate specificity: P5 is targeted to BiP client proteins.
abstract: At least 17 members of the protein disulphide isomerase (PDI) family of oxidoreductases are present in the endoplasmic reticulum (ER) of mammalian cells. They are thought to catalyse disulphide formation to aid folding or to regulate protein function; however, little is known about their individual functions. Here, we show that some proteins that enter the ER are clients for single oxidoreductases, whereas others are clients for several PDI-like enzymes. We previously identified potential substrates for ERp57, and here identify substrates for ERp18 and ERp46. In addition, we analysed the specificity of substrates towards PDI, ERp72, ERp57, ERp46, ERp18 and P5. Strikingly, ERp18 shows specificity towards a component of the complement cascade, pentraxin-related protein PTX3, whereas ERp46 has specificity towards peroxiredoxin-4, a thioredoxin peroxidase. By contrast, most PDI family members react with Ero1alpha. Moreover, P5 forms a non-covalent complex with immunoglobulin heavy chain binding protein (BiP) and shows specificity towards BiP client proteins. These findings highlight cooperation between BiP and P5, and demonstrate that individual PDI family members recognise specific substrate proteins.
authors.affiliation: Faculty of Life Sciences, Michael Smith Building, University of Manchester, Manchester, M13 9PT, UK.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Jessop
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Watkins
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Simmons
authors.forename: Mohammed
authors.initials: M
authors.lastname: Tasab
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Bulleid
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D015180:Electrophoresis, Gel, Two-Dimensional; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D011485:Protein Binding; D011490:Protein Disulfide Reductase (Glutathione) / Q000235:genetics / Q000378:metabolism; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D011490:Protein Disulfide Reductase (Glutathione); C477009:TXNDC12 protein, human; D019704:Protein Disulfide-Isomerases; C480743:TXNDC5 protein, human