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Faculty Lecture Series


When

Wednesday, November 11, 2009
5 PM - 6 PM

Where

Valerie Timken Amphitheater
Green Hospital

Who

Jeffery Kelly, Ph.D.
Lita Annenberg Hazen Professor of Chemistry
Chairman, Department of Molecular and Experimental Medicine
Member, Ths Skaggs Institute for Chemical Biology

Topic

"Proteostasis"
  The chemical information within the polypeptide chain, co- and post-translational modifications of the amino acids comprising the protein, including N-linked glycosylation, and the interactions of the polypeptide with proteostasis network components determine whether a given member of the proteome will fold and function, be degraded, remain natively unfolded or aggregate and create additional proteostatic challenges for the organism. The outset of the seminar will focus on the intrinsic forces that predispose polypeptides to fold, including conformational propensities, hydrogen bonding, the hydrophobic effect as well as the influence of post-translational modifications. The second part of the talk will focus on the extrinsic forces that assist and enable proteome maintenance, and the means by which the proteostasis network enhances protein structure acquisition, function and clearance to facilitate life and avoid loss- and gain-of-function diseases. The influence of the proteostasis network, comprising transcriptional and translational control of protein synthesis, chaperone- and enzyme-assisted folding, disaggregation activities and degradation activities will be covered. Furthermore, the influence of aging-associated signaling pathways on proteome maintenance will be discussed. The lecture will close with a summary of what we have learned about degenerative diseases associated with protein aggregation and loss-of-function diseases associated with excessive mutant protein misfolding and degradation. Specifically, we will focus on how we are ameliorating these diseases with Proteostasis Regulators, small molecules that readapt the innate biology of proteostasis through signaling pathways that control the Proteostasis Network. Synergistic rescue of protein homeostasis through the use of Pharmacologic Chaperones and Proteostasis Regulators and the demonstration that one Proteostasis Regulator can be used to intervene in multiple protein misfolding diseases will be demonstrated.

Selected Publications

  Balch, W.E.; Morimoto, R.I.; Dillin, A.; Kelly, J.W. "Adapting Proteostasis For Disease Intervention" Science 2008 319, 916-919
  Mu, T-W.; Ong, D.S.T.; Wang, Y-J; Balch, W. E.; Yates, J.R.; Segatori, L.; Kelly, J.W. "Chemical and Biological Approaches Synergize to Ameliorate Protein-Folding Diseases" Cell 2008 134, 769-781.
  Mu, T-W.; Fowler, D. M.; Kelly, J. W. "Partial Restoration of Mutant Enzyme Homeostasis in Three Distinct Lysosomal Storage Disease Cell Lines by Altering Calcium Homeostasis" PloS Biol. 2008 6, 253-265, e26
  Wiseman, R.L.; Powers, E.T.; Buxbaum, J.N.; Kelly, J.W.; Balch, W.E. "An Adaptable Standard For Protein Export from the Endoplasmic Reticulum" Cell 2007 131, 809-821.