The Origin of Specificity in Regulated Protein Degradation

One of the characteristic features of life is specificity. It emerges in metabolism, information transfer from DNA to protein, embryology, immunology and virtually every other process. Its explanation on the molecular level is thermodynamic stability and structural complementarity. Yet one disturbing issue persists: the protein and nucleic acid sequences coding for that specificity are generally too small to distinguish actual partners from competitors. Similarly, protein degradation conveys specificity through very short sequences. The process is so kinetically complex that bulk kinetic experiments and a few molecular structures are insufficient to explain how specificity is achieved. Using single molecule kinetic measurements, we have deconvolved much of that specificity. The results reveal a novel process based loosely on some original ideas of kinetic proofreading, by John Hopfield and Jacques Ninio. The unraveling of the details of the ubiquitin mechanism has led us to think more generally about the tradeoffs in biology between specificity and speed and the limits to which energy consumption can optimize that tradeoff. These conclusions based on understanding the mechanism of protein degradation may be relevant to other biochemical processes, such as phosphorylation and transcription.

Marc W. Kirschner, Ph.D. graduated from Northwestern University in 1966 and received his Ph.D. from the University of California, Berkeley in 1971. Following postdoctoral research at Berkeley and at the University of Oxford, he was appointed as Assistant Professor at Princeton University in 1972 and full Professor in 1978. In 1978, he moved to the Department of Biochemistry and Biophysics at the University of California, San Francisco as a Professor. After fifteen years at the University of California, San Francisco, Dr. Kirschner moved to Harvard Medical School in 1993 to become the founding Chair of the Department of Cell Biology. In 2003, he established the Department of Systems Biology at Harvard Medical School and became its first Chair. In 2009 he was named University Professor, Harvard’s highest professorial distinction.

Dr. Kirschner’s laboratory investigates three broad, diverse areas: regulation of the cell cycle, the role of cytoskeleton in cell morphogenesis, and mechanisms of establishing the basic vertebrate body plan.