Center for Protein Folding Machinery
Wah Chiu, Ph.D., Baylor College of Medicine
William Mobley, M.D., Ph.D., University of California, San Diego
Eric Jonasch, M.D., MD Anderson Cancer Center
Judith Frydman, Ph.D., Stanford University
The Center for Protein Folding Machinery is developing therapeutic strategies for Huntington’s disease (HD) and Von Hippel-Lindau (VHL) disease by harnessing understanding of chaperonin mechanism and function.
This center began with a broad goal of understanding eukaryotic protein folding as a foundation for designing chaperonin-based nanomachines with novel therapeutic functions. They focused on protein folding chaperones such as type II molecular chaperonins, specifically, the eukaryotic chaperonin, TRiC/CCT and the archaebacterial chaperonin, Mm-cpn. Initial characterization of the biophysical properties and functions of chaperonins and their substrates included generation of an atomic model of TRiC, and imaging chaperonin bound with substrate proteins in vitro and in cells.
Several human diseases are associated with misfolded proteins, and the center elected to focus on two clinical targets, Huntington’s disease (HD) and Von Hippel-Lindau (VHL) disease. They discovered that TRiC is a potent inhibitor of Huntingtin protein aggregation, and observed a direct interaction between TRiC and pVHL.
To achieve their goals of treating HD and VHL disease, the center is developing chaperonin-inspired therapeutics and/or substrate adaptor molecules to prevent aggregation and/or return misfolded proteins to normal. Their approach includes developing and integrating new methods to characterize the biophysical and biochemical properties of chaperonins.
Both HD and VHL disease arise as a consequence of well-defined genetic lesions which cause misfolding of chaperonin substrates. However, the underlying molecular nature of their pathology is distinct: HD features the aggregation of a mutant protein that triggers a cascade of pathogenic mechanisms that appear to result in both gain of toxic function and loss of normal function; in contrast, VHL disease arises from the loss-of-function of a folding-defective mutant protein. The translational approaches to remedy each disease through chaperonin-based intervention thus differ. In the case of HD, the center will use the eukaryotic chaperonin and/or engineered chaperonin-derivatives to prevent the cellular toxicity associated with protein aggregation. However, for VHL Disease, they will exploit their knowledge of chaperonin-mediated action to promote pVHL refolding and restore functionality to tumor-promoting mutants.
CLINICAL CONSULTING BOARD (CCB)
Steven Finkbeiner, M.D., Ph.D., University of California, San Francisco
Jeff W. Kelly, Ph.D., Scripps Research Institute
Leonard M. Neckers, Ph.D., National Cancer Institute
M. Kimryn Rathmell, M.D., Ph.D., University of North Carolina
William Yang, M.D., Ph.D., University of California, Los Angeles