Areas of Interest
Our research focuses on understanding how the cell cycle is
regulated by ubiquitin-mediated proteolysis using x-ray
crystallography as a primary tool. Progression through the cell
cycle is coordinated by the cyclin-dependent kinases (CDKs) and
their activating cyclin subunits as well as a series of CKI
inhibitors. Control of the oscillations of the cyclins and CKIs
by ubiquitin-dependent proteolysis plays a critical role in cell
cycle regulation. Deregulation of the cyclins and CKIs can cause
aberrant proliferation and genomic instability. Indeed, the
eukaryotic cell cycle is one of the most frequently altered
cellular processes identified in cancer.
Proteins degraded by the ubiquitin-mediated proteolysis must
be covalently linked to the small protein ubiquitin. Ubiquitin
serves as a molecular tag that marks proteins for degradation by
the 26S proteasome. The selection of substrates for
ubiquitination is prescribed by a specific class of enzymes
called ubiquitin-protein ligases (also known as E3s). Most E3
ligases comprise a large superfamily of protein-protein
complexes. They bind the substrate protein and a cognate
ubiquitin-conjugating enzyme (E2), and catalyze the transfer of
ubiquitin from the E2 to specific lysine residues within the
substrate. Thus E3s are responsible for both ubiquitin transfer
and specific recognition of each of the target proteins.
However, the molecular details underlying these two processes
remain poorly understood.
The overall goal of our research is to use SCF ubiquitin
ligases as a model system to elucidate the structural and
mechanistic basis of substrate recognition, lysine specificity,
ubiquitin transfer, and the role of CDK in CKI degradation. Our
long-term objective is to gain a detailed understanding of the
structure, function, and regulation of APC/C and Cul3-based
ubiquitin ligases, and to use this knowledge to elucidate how
defects of the ubiquitin system can lead to cancer and
neurodegenerative diseases.
If you are interested in conducting postdoctoral or graduate
research in our laboratory or would like more information,
please contact Bing Hao at
bhao@uchc.edu.
Lab Rotation Projects
- Elucidation of the mechanism that regulates the
substrate lysine selection by E2 and E3 during ubiquitin
transfer.
- Structural characterization of the E2-SCF E3 interaction
and its role in the ubiquitin transfer process.
- Structural studies of the SCF E3-substrate complexes.
Selected Publications
Bing Hao, Stephanie Oehlmann, Mathew E. Sowa, J. Wade Harper,
and Nikola P. Pavletich (2007). Structure of a Fbw7-Skp1-CyclinE
complex: multisite-phosphorylated substrate recognition by SCF
ubiquitin ligases. Mol Cell 26, 131-143 (cover story).
Bing Hao, Ning Zhang, Brenda A. Schulman, Geng Wu, Julie J.
Miller, Michele Pagano, and Nikola P. Pavletich (2005).
Structural basis of the Cks1-dependent recognition of p27Kip1 by
the SCFSkp2 ubiquitin ligase. Mol. Cell 20, 9-19.
Bing Hao, Gang Zhao, Patrick Kang, Jitesh Soares, Tsuneo K.
Ferguson, Judith Gallucci, Joseph A. Krzycki, and Michael K.
Chan (2004). Reactivity and synthesis of L-pyrrolysine- the 22nd
genetically-encoded amino acid. Chemistry & Biology 11, 1317-24.
Bing Hao, Clara Isaza, Joseph Arndt, Michael Soltis, and
Michael K. Chan (2002). Structure-based mechanism of O2 sensing
and ligand discrimination by the FixL heme domain of
Bradyrhizobium japonicum. Biochemistry 41, 12952-8.
Bing Hao, Weimin Gong, Tsuneo K. Ferguson, Carey M. James,
Joseph A. Krzycki, and Michael K. Chan (2002). A new UAG-encoded
residue in the structure of a methanogen methyltransferase.
Science 296, 1462-6 |
