Hiram F. Gilbert, Ph.D.
Professor, Biochemistry & Molecular Biology
Education and Awards
- Ph.D., Organic Chemistry, 1975, University of Wisconsin
- Postdoctoral, 1975-1979, Brandeis University
- Research Career Development Award, National Institutes of Health, 1982-1986
Catalysis of Protein Folding
The information that directs a newly synthesized protein to fold into its proper three-dimensional structure is contained within the primary sequence of the protein. Whereas, some proteins will spontaneously adopt their correct structures, there are some proteins that require the assistance of molecular chaperones and folding catalysts to fold rapidly and correctly. Reduced, denatured proteins often form large, insoluble aggregates in solution because the exposed hydrophobic residues associate promiscuously with each other. Understanding the mechanisms by which folding catalysts and chaperones facilitate correct folding is a challenging mechanistic and structural problem with obvious importance to the production of correctly folded recombinant proteins for therapeutic and research uses. Protein disulfide isomerase (PDI) is an abundant 57-kDa protein that resides in the lumen of the endoplasmic reticulum and catalyzes the formation and rearrangements of disulfide bonds in secreted proteins. PDI also serves as a molecular chaperone that can inhibit protein aggregation. It is a modular protein composed of four, tandem thioredoxin structural domains. The two outer domains (a and a') are catalytic and provide the redox function for making and breaking disulfides. The two inner domains (b and b') are thought to provide some of the non-covalent interactions with substrates. Our studies are focusing on the structural basis of the biological and biochemical activities of this remarkable class of folding catalysts through mutagenesis and mechanistic approaches coupled to genetic and biochemical studies to study disulfide formation and rearrangements in Saccharomyces cerevisiae as part of the secretion pathway.