The unifying theme of our research focuses on the biochemistry and structural biology of macromolecular machines. One of the model systems we have chosen is the human mitochondrial pyruvate dehydrogenase complex (PDC) that converts pyruvate to acetyl-CoA, linking glycolysis to lipogenic and steroidogenic pathways. PDC is a 9.5-megadalton catalytic machine organized around a 60-meric acetyltranferase (E2p) core, to which multiple copies of pyruvate dehydrogenase (E1p), dihydrolipoamide dehydrogenase (E3), E3-binding protein, a specific kinase and a specific phosphatase are attached. We are deciphering how different enzyme components in this catalytic machine interact with each other to achieve substrate channeling and regulation by phosphorylation. We are also interested in how chaperonin machines such as bacterial GroEL/GroES and mitochondrial Hsp60/Hsp10 promote the folding and assembly of large protein complexes. State-of-the-art methods such as X-ray crystallography, multi-dimensional NMR spectroscopy, cryo-electron microscopy and isothermal titration calorimetry are employed in these studies. Knowledge derived from the PDC research will provide the structural basis for dysfunction of this catalytic machine, which is implicated in human disease such as neonatal lactic acidemias, encephalopathies and type 2 diabetes. The information on the mechanism of chaperonin action, on the other hand, will help understand protein misfolding as a culprit of neurodegenerative disorders.
RESEARCH INTERESTS
Chaperone-mediated biogenesis of mitochondrial multi-enzyme complexes.
Structure and protein-protein interactions of mitochondrial multienzyme complexes.
Molecular genetic and biochemical basis of maple syrup urine disease.
RECENT PUBLICATIONS
Kato, M., Chuang, J.L., Tso, S.-C., Wynn, R.M., and Chuang, D.T., "Crystal structure of pyruvate dehydrogenase kinase 3 bound to lipoyl domain 2 of the human pyruvate dehydrogenase complex." EMBO J., 24:1763-1774, 2005
Brautigam, C. A., Chuang, J. L., Tomchick, D. R., Machius, M. and Chuang, D. T., "Crystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH binding and the structural basis of disease-causing mutations." J. Mol. Biol., 350:543-552, 2005
Wynn, R.M., Kato, M., Machius, M., Chuang J.L., Li J, Tomchick D.R., and Chuang, D.T., "Molecular mechanism for regulation of the human mitochondrial branched-chain a-ketoacid dehydrogenase complex by phosphorylation." Structure, 12:2185-2196, 2004
Ludtke, S., Chen, D., Song, J.-L., Chuang, D.T., and Chiu, W., "Seeing GroEL at 6 ? resolution by single particle electron cryomicroscopy." Structure, 12:1129-1136, 2004
Li, J., Wynn, R. M., Machius, M., Chuang, J. L., Karthikeyan, S., Tomchick, D. R., and Chuang, D. T., "Crosstalk between thiamin diphosphate binding and phosphorylation loop conformation in human branched-chain a-ketoacid decarboxylase/dehydrogenase." J. Biol. Chem., 279:32968-32978, 2004
SIGNIFICANT PUBLICATIONS
Aevarsson, A., Chuang, J.L., Wynn, R.M., Turley, S., Chuang, D.T., and Hol, W.G.H., "Crystal structure of human branched-chain (alpha)-ketoacid dehydrogenase and molecular basis of multienzyme complex deficiency in maple syrup urine disease." Structure, 8:277-291, 2000
Chang, C.-F., Chous, H.-T., Chuang, J.L., Chuang, D.T., and Huang, T.-H., "Solution structure of the lipoic acid-bearing domain of human mitochondrial branched-chain (alpha)-ketoacid dehydrogenase complex." J. Biol. Chem., 277:15865-15873, 2002
Song, J..-L., Li, J., Huang, Y.-S., and Chuang, D.T., "Encapsulation of an 86-kDa Assembly Intermediate inside the Cavities of GroEL and Its Single-ring Variant SR1 by GroES." J. Biol. Chem., 278:2515-2521, 2003
Song, J.-L., and Chuang, D.T., "Natural osmolyte trimethylamine N-oxide corrects assembly defects of mutant branched-chain (alpha)-ketoacid dehydrogenase in maple syrup urine disease." J. Biol. Chem., 276:40241-40246, 2001
Machius, M., Chuang, J.L., Wynn, R.M., Tomchick, D.R., and Chuang, D.T., "Structure of rat BCKD kinase: nucleotide-induced domain communication in a mitochondrial protein kinase." Proc. Natl. Acad. Sci. USA, 98:11218-11223, 2001
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