ABSTRACT
Research School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK
*Corresponding author
1. Introduction 2. Molecular Properties of PDI 2.1. Analysis of PDI Protein Sequences 2.2. Evidence for the Domain Organization of Mammalian PDI 2.3. PDI as a Member of the Thioredoxin Superfamily of Proteins 2.4. Chemical Properties of the Thioredoxin-like Domains within PDI 3. PDI as a Catalyst of Thiol:disulphide Interchange and Protein Folding 3.1. Activity Towards Simple Peptide Substrates 3.2. Activity Towards Well-Defined Protein Substrates 3.3. Activities of Mutant PDIs and Domains 3.4. Does PDI Catalyse Folding or Just the Disulphide-Isomerizations Associated with Folding? 4. Binding Properties of PDI 4.1. Interaction of PDI with Non-Peptides 4.1.1. Interaction of PDI with Thyroid Hormone 4.1.2. Interaction of PDI with Oestrogens 4.2. Interaction of PDI with Peptides and Proteins 4.2.1. Interaction of PDI with Peptides 4.2.2. Interaction of PDI with Proteins 4.2.3. Interaction of PDI with ER Proteins 5. Is PDI a Molecular Chaperone? 6. References
1. INTRODUCTION
Protein disulphide-isomerase (PDI), an enzyme found in the endoplasmic reticulum of eukaryotic cells, was the first catalyst of protein folding to be identified. In their initial studies on protein refolding in vitro, Anfinsen and colleagues recognised that the conditions required for successful refolding of reduced ribonuclease (high dilution, high pH etc.) were not physiological, and that the time-scales involved (hours to days) were much longer than those for protein folding in the cell (Epstein et al., 1963). They inferred that the process was catalysed in the cell and sought potential cellular catalysts. In the mid 1960s, they and other groups showed that refolding of reduced ribonuclease and other proteins could be catalysed by microsomal preparations from vertebrate secretory tissues such as liver, pancreas etc. (Goldberger et al., 1963), purified the enzyme responsible (DeLorenzo et al., 1966) and proposed a role for it in protein folding in the cell (Givol et al., 1964). The catalytic properties of the purified enzyme from mammalian liver were described over the next 10 years, and were consistent with its being involved in the catalysis of native disulphide bond formation during the folding of nascent secretory proteins.
