The unifying theme of our research focuses on the biochemistry and structural biology of macromolecular machines. These large interlocking protein machines carry out complex biological functions in a highly coordinated fashion. We have chosen human mitochondrial branched-chain alpha-ketoacid dehydrogenase (BCKD) complex as a model system to shed light on how different enzyme components in this 4-megadalton metabolic machine interact with each other to achieve substrate channeling and regulation by phosphorylation. We are also interested in how the mitochondrial chaperonin machine assists in the folding and assembly of protein components in other macromolecular machines such as those in the BCKD complex. State-of-the-art methods employed for these studies include X-ray crystallography, multi-dimensional NMR spectroscopy, cryo-electron microscopy and isothermal titration calorimetry. Specifically, our three research projects are:
Knowledge derived from the above investigations will provide a structural basis for the dysfunction of the BCKD metabolic machine which results in heritable Maple Syrup Urine Disease, and help understand protein misfolding as a culprit of neurodegenerative disorders.