STRUCTURAL STUDIES OF PROTEIN DISULFIDE ISOMERASES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Protein chaperones, called protein disulfide isomerases (PDI), represent a key step in the folding of proteins. They oxidize cysteine residues in proteins and assure the correct the arrangement of disulfide bonds. In spite of their importance, the mechanism of action of PDIs is poorly understood. More than a dozen human PDIs have been identified. Some are specific for folding certain proteins; others appear to be general in action. One of the goals of the proposed work is to understand the origin of substrate specificity among PDIs. A second goal is to understand the catalytic mechanism which involves both the formation of disulfide bonds (oxidation) and their correct organization (isomeration). We recently determined the three dimensional structure of a specific PDI, ERp57, which is involved in assembly of the major histocompatibility complex MHC-I. We will carry out structural studies of different PDI`s in order to learn more about their three dimensional shape and function. The proposed research will aid our understanding of the entry into the cells of viruses and diseases that result from misfolding of proteins.