Robert T. Sauer

My long-term interest has been to understand how the sequence of a protein directs the acquisition of the correct three-dimensional fold and how sequence and structure mediate the highly specific molecular recognition events that are crucial in living cells. As model systems, we have focused on the structure, folding, and function of small repressor proteins, such as the Arc repressor of bacteriophage P22, using protein biochemistry, mutagenesis, fast kinetics, thermodynamic analyses, molecular design, and x-ray crystallography. These studies have identified a subset of amino acids that carry the great majority of the information needed for protein folding, have shown that this information is highly context-dependent, and have generated mutant proteins with super-fast and super-stable folding phenotypes as well as with dramatically altered DNA-binding specificities. While studying the expression of thermodynamically unstable mutant proteins, we discovered that cells contain endoproteases that degrade proteins based upon the nature of their C-terminal sequences. Recent studies have shown that one of the functions of these enzymes is to rid the cell of potentially damaging polypeptides that are marked for destruction by cotranslational addition of a C-terminal peptide tag, which is encoded by a nucleic acid molecule that functions both as a transfer-RNA and as a messenger-RNA.