Most proteins are chemically modified after they are made to control how, when, and where they function. It was thought that only the amino acid side chains and the peptide bonds of proteins were chemically modified. It has become clear in recent years that the disulfide bonds of proteins are also modified. Some disulfide bonds are cleaved in the mature protein to control function. From a few examples a decade ago, there are now about thirty well-defined examples of control of protein function by functional disulfides and dozens more examples that are under investigation. Cleavage of a functional disulfide in a protein changes the bioactivity of the protein. Changes in ligand binding, substrate hydrolysis, proteolysis, or oligomer formation have been described. The functional disulfides are cleaved by reductases or by thiol–disulfide exchange. Viral, bacterial, plant and mammalian proteins are regulated by functional disulfides, so this mechanism of protein control operates in all life forms. The early indications are that cleavage of disulfide bonds may rival proteolysis of peptide bonds as a means of protein control.
This conference will focus on the functional disulfides that contribute to regulation of thrombosis, neuroprotection and cancer in mammals. How protein function in these systems is regulated by disulfide bond cleavage and the factors that cleave the bonds will be discussed. The chemistry and molecular dynamics of cleavage of functional disulfides will be addressed, and the bioinformatic and experimental approaches used to identify and study these bonds will be examined. Some functional disulfides have been linked to human disease and progress is being made on ways of targeting these bonds for new diagnostics and therapies. Small molecule inhibitors of the factors that cleave functional disulfides are in pre-clinical and clinical development.
The invited presentations will be from both established and junior investigators and a large number of oral presentations will be selected from the abstracts. The talks, poster presentations and recreational activities will provide students and postdoctoral fellows with opportunities to exchange ideas, formulate new collaborations and explore career options in this research field.