Our research is aimed at understanding the function of biological macromolecules via structural analyses, primarily by cryo-electron microscopy. Cryo-EM is capable of revealing low to medium resolution structures of large protein complexes that are proven difficult for X-ray crystallography or NMR methods.
Structural basis of eukaryotic DNA replication initiation
The yeast origin recognition complex (ORC) is a six-protein assembly discovered in 1992 in the lab of Bruce Stillman at Cold Spring Harbor Laboratory. ORC is conserved in all eukaryotes from yeast to human. Yeast ORC constitutively binds to and marks the replication origin throughout the cell cycle. Licensing of the DNA replication origin starts when the cell division cycle protein Cdc6p binds to ORC. Despite recent breakthrough in structures of prokaryotic replication initiators, structural information on eukaryotic ORC has been rather limited. My lab has been investigating the structural basis of the yeast DNA replication initiation by cryo-EM method.
The M. tuberculosis proteasome pathway
Proteasome is widespread in eukaryotes and archaea, but very rare in eubacteria. Recently, the bacterium M. tuberculosis (Mtb) was found to possess a ubiquitin-like proteasome pathway. Furthermore proteasome was found to be required for Mtb resistance to killing by the host immune system. Proteasome and proteasomal ATPase appear to protect Mtb against nitric oxide from macrophage by degrading damaged proteins after exposure to nitric oxide. Thus, Mpa and the Mtb proteasome may be promising targets for the development of anti-TB chemotherapeutics. We study the structure and inhibition of the Mtb proteasome system.
Structural biology of membrane protein assemblies
We have been collaborating with David Thanassi group in Microbiology department on cryo-EM of the PapC usher, a bacterial outer membrane protein that orderly secrets and assembles the bacterial surface pili. We also image the yeast oligosaccharyl transferase, a nine-protein complex that glycosylates the nascent polypeptide chains at the endoplasmic reticulum membrane. This work is in collaboration with Bill Lennarz’s lab in this department. Another interesting project that we are working with Dennis Selkoe and Michael Wolfe groups at Harvard Medical School is the human γ-secretase. Gamma-Secretase is an intramembranous aspartyl protease that is required for the processing of many membrane proteins, including Notch and amyloid precursor protein.
Top of Page