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• W1566110664 abstract "The Structural Stability of a Protein Is an Important Determinant of Its Proteolytic Stability in Escherichia coli(Parsell, D. A., and Sauer, R. T. (1989) J. Biol. Chem. 264, 7590–7595)Identification of C-terminal Extensions That Protect Proteins from Intracellular Proteolysis(Bowie, J. U., and Sauer, R. T. (1989) J. Biol. Chem. 264, 7596–7602) The Structural Stability of a Protein Is an Important Determinant of Its Proteolytic Stability in Escherichia coli (Parsell, D. A., and Sauer, R. T. (1989) J. Biol. Chem. 264, 7590–7595) Identification of C-terminal Extensions That Protect Proteins from Intracellular Proteolysis (Bowie, J. U., and Sauer, R. T. (1989) J. Biol. Chem. 264, 7596–7602) Robert T. Sauer grew up in the Hudson River Valley in New York. He attended Amherst College and received his B.A. in biophysics in 1972. Before and after graduating from Amherst, he worked as a research technician at Massachusetts General Hospital in Boston. Eventually, Sauer enrolled in graduate school at Harvard University. His Ph.D. research focused on how the modular structure of phage λ repressor allowed it to act as a regulator of gene expression. A year before receiving his Ph.D. in 1979, Sauer joined the biology department at Massachusetts Institute of Technology (MIT). He worked his way up through the academic ranks and eventually became Salvador E. Luria Professor of Biology, a title that he continues to hold today. When he started his lab at MIT, Sauer continued his research on the regulation of gene expression, studying the mechanisms that allow transcription factors to recognize their specific binding sites in chromosomal DNA. Over the years, his interests shifted to protein folding and how amino acid sequence dictates the three-dimensional structure, stability, and susceptibility of proteins to degradation. Some of his findings are detailed in the two papers reprinted here that were published back to back in the Journal of Biological Chemistry (JBC). At the time the papers were published, it was believed that the proteolytic susceptibility of a protein was related to the thermodynamic stability of its native structure. However, it was difficult to prove this hypothesis because experiments inevitably ended up altering more than one property of the protein being studied. For example, a side chain modification meant to alter protein stability could also affect degradation if it acted as a recognition signal. As detailed in the first Classic, Sauer and his graduate student Dawn Parsell came up with a system in which they could alter protein stability without changing other variables. They constructed a set of variants of the N-terminal DNA-binding domain of λ repressor with a wide range of melting temperatures. Pulse-chase experiments showed that the most thermally stable proteins had the longest intracellular half-lives. The pair also showed that second-site mutations that increased the thermodynamic stability of the native N-terminal domain also suppressed intracellular degradation. This paper was followed by one in which Sauer and his graduate student James Bowie showed that intracellular degradation can also be affected by mechanisms independent of a protein's thermodynamic stability. The scientists isolated revertants of defective mutants in the Arc repressor of bacteriophage P22 and found that five of the six reverting mutations were frameshifts resulting in C-terminal extensions. The mutations prolonged the half-lives of the proteins but did not alter their thermodynamic stability, structure, oligomeric form, or DNA-binding properties. Furthermore, fusion of one of these tails to the C-terminal end of a mutant form of the N-terminal domain of λ repressor prevented proteolysis of the protein. Sauer hypothesized that the C-terminal sequences prevented degradation by blocking the proteins' recognition by the cell's proteolytic machinery. From these experiments, Sauer proposed a bipartite model for protein turnover in which the thermodynamic stability of a protein determines the fraction of the protein that will be in an unfolded and proteolytically susceptible state, whereas sequence determinants within the unfolded protein chain determine how effectively it will act as a substrate for proteolytic enzymes. Most recently, Sauer's research has focused on the structure and function of the molecular machines that disassemble macromolecular complexes and unfold native proteins. Sauer has received many honors and awards in recognition of his contributions to science and teaching. These include the MIT School of Science Prize for Excellence in Graduate Teaching (1998), the Protein Society's Amgen Award (2001) and Hans Neurath Award (2007), and election to the American Academy of Arts and Sciences (1993), the National Academy of Sciences (1996), and the American Academy of Microbiology (1996). He also served as president of the Protein Society (1997–1999) and head of the MIT Department of Biology (1999–2004)." @default.
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• W1566110664 title "A Model for Protein Turnover: the Work of Robert T. Sauer" @default.
• W1566110664 doi "https://doi.org/10.1016/s0021-9258(20)37726-7" @default.
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