研究・研究者
研究会・セミナー
| 演 題 | 「Allostery and Recruitment in the E3 Ligase gp78: Combined Structural and Molecular Biology」 |
|---|---|
| 日 時 | 2012年10月11日(木) 15:00 |
| 講演者 | R. Andrew Byrd (Chief, Structural Biophysics Laboratory,Center for Cancer Research National Cancer Institute) |
| 場 所 | 山手3号館2階西 共通セミナー室 |
| 概 要 | The post-translational modification of proteins by chains of ubiquitin molecules has long been known to play several functions in the inducible and reversible control of signaling pathways. Since numerous cellular functions can be regulated by ubiquitylation and rapid protein turnover, the ubiquitin system suggests highly attractive drug targets for the development of anti-cancer treatments. A comprehensive understanding of the ubiquitin-modification process is the key to initiating effective intervention or modulation. Ubiquitylation is a multistep process where several classes of enzymes function in a sequential regulated manner. First, ubiquitin is activated by an activating enzyme (E1). The activated ubiquitin is then conjugated to the conjugating enzymes (E2s). The E2s interact with another class of proteins known as ubiquitin ligase (E3s), which function to transfer ubiquitin to the targeted protein. The E2:E3 pair recruit substrates for ubiquitination, and this cycle repeats to create poly-ubiquitin chains that impart the signaling fate. A majority of E3s have an internal domain, known as a RING finger, which binds weakly to E2s and allows ubiquitylation to proceed. However, some RING finger E3s have a supplementary region that recruits the cognate E2. The structural and functional implication of this new binding site has been investigated through a combination of structural, biophysical and biochemical studies of the E2:E3 pair Ube2g2:gp78. We have recently characterized the two E2-interacting domains in gp78, RING finger and G2BR, and their diverse, synergistic effects on Ube2g2. We have also examined recruitment via a ubiquitin-interacting domain CUE. These mechanistic insights suggest alternate therapeutic avenues in cancer and other diseases. |
