Protein Folding, Misfolding, Chaperonins and Human Disease

MIT Subaward from Baylor College of Medicine as part of the NIH/NEI Award #EY016525, "Center for Protein Folding Machinery"

The Center for Protein Folding Machinery is aimed at developing the capabilities of engineering protein folding nanomachine so that it will fold any protein of biomedical and biotechnological interests, and of designing new substrates to be folded efficiently in the naturally occurring or engineered chaperone. In the first 5 year, we would like to demonstrate the feasibility of engineering the mammalian chaperonin, TRiC from cow and its closest archaeal homolog, Mm-cpn from M. maripaludis to fold a number of substrates including actin, cancer related proteins such as p53 and VHL suppressor protein, and the aggregated proteins such as the A-beta peptide and the cataract related protein, alpha-crystallin. In addition, we will develop the design of adaptor peptides to modify the substrates in order to enhance the substrate and chaperone interaction resulting in a more efficient folding. We adopt the approach of developing a protein design strategy based on features and dynamics characteristics of the chaperonins and their complexes with the substrates. We have assembled a team of 15 investigators from 8 institutions with a diverse expertise in chaperone biology, protein folding, electron cryomicroscopy, x-ray crystallography and scattering, single-molecule imaging and spectroscopy, modeling, and translational research in cancer. We propose to establish an integrated toolbox of experimental and computational methodologies which will be used as analytic, predictive and diagnostic tools during the discovery process of engineering a new product, which is iterative and high throughput. Because of the complexity and conformationally varying nature of chaperonin under consideration (e.g. ~1 mDa), we need to refine and validate the existing methodologies for measurements in both in vitro and in vivo. Our new toolbox will be useful for studying nanomachines of any types. We plan to interact with other NDC with complementary expertise in synthetic chemistry and other novel technology. Through our clinical investigator, we will make inroads to put our engineered products into medical and biotechnological usages that would cure cancer and protein aggregation diseases such as Parkinson and Alzheimer's. The organization of our NDC exemplifies the 21st century of virtual reality of conducting complex and interdisciplinary research via new mechanism of data sharing and comunications. We also make a strong commitment in educational outreach by offering a virtual course in nanodmedicine.

Link to the Center for Protein Folding Machinery website.


For King Lab publications on this topic, look under Protein Aggregation & Misfolding and Protein Folding & Stability categories of the Publication by Category webpage.