[4-22]Dynamic assembly/disassembly of the CRL-CSN complexes mediated by inositol hexakisphosphate and its metabolic enzymes

报告题目：Dynamic assembly/disassembly of the CRL-CSN complexes mediated by inositol hexakisphosphate and its metabolic enzymes

报 告 人：饶枫 研究员（北京生命科学研究所）

报告时间：2016年4月22日（星期五）下午3:00
报告地点：独墅湖校区二期云轩楼2301室

报告摘要：
The family of Cullin-Ring ubiquitin ligases (CRLs) mediates the turnover of 20% of the proteome. CRLs ubiquitylate numerous substrates involved in cell fate and organelle homeostasis, commending their being emerging therapeutic targets. CRLs require neddylation, the attachment of an ubiquitin-like NEDD8 molecule, for optimal function and are tightly regulated by the deneddylase COP9 signalosome (CSN). CSN biochemically inhibits but genetically activates CRLs. Elucidating the mechanism of binding and dynamic assembly/disassembly of the Cullin-CSN complexes is therefore key to understand physiological regulation of CRLs. We now delineate Cullin-CSN interaction mechanisms, demonstrating an essential electrostatic interaction between the N-terminal acidic tail of CSN subunit 2 (CSN2) and a conserved basic canyon on cullins. Furthermore, we discover that IP6, at nanomolar potency, mediate interactions between CSN2 and Cullins to facilitate the assembly of CRL-CSN complexes. The IP6 synthase IP5K binds to CRL and regulates their physiological function (PNAS 2016, early edition). Together with our earlier studies showing that IP6K1 metabolizes IP6 to trigger disassembly of CRL4-CSN complexes (PNAS, 2014, 16005), these findings establish that IP6, in conjunction with its metabolizing enzymes, determines the stability, activity and dynamics of Cullin-CSN complexes.

报告人简介：
饶枫博士：新加坡国立大学获得本科学位，南洋理工大学获得博士学位，Johns Hopkins大学从事博士后研究，2015年加入北京生命科学研究所。在Mol. Cell, PNAS, JBC发表多篇学术论文。

代表性论文：

1.      Scherer, P.#, Ding, Y.#, et al,, Snyder, SH*, Rao, F.* Inositol hexakisphosphate generated by IP5K mediates cullin-COP9 signalosome interactions and CRL function. Proc. Natl. Acad. Sci. 2016 (Accepted)

2.      Rao F.#, Xu, J.#, Fu, C., Cha， J., Xu, R., Gadalla, MM., Wu, M., Fiedler, D., Barrow, JC., Snyder, SH. Inositol pyrophosphates promote cancer growth and metastasis by antagonizing the tumor suppressor LKB1.  Proc. Natl. Acad. Sci. 2015 112, 1773-8. (Highlighted by Chemistry & Biology)

3.      Rao F.#, Xu, J.#, Kahn, AB., Cha, J., Xu, R. Tyagi, R., Dang, Y., Chakraborty, A., Snyder, SH. Inositol hexakisphosphate kinase-1 mediates assembly/ disassembly of the CRL4-Signalosome complex to regulate DNA repair and cell death. Proc. Natl. Acad. Sci. 2014 111, 16005-16010.

4.      Rao F., Cha, J., Xu, J., Xu, R., Vandiver, MS., Tokhunt, RT., Wu, M., Fiedler, D., Barrow, J., Snyder, SH. Inositol pyrophosphates mediate the DNA-PK/ATM-p53 cell death pathway by regulating CK2 phosphorylation of Tti1/Tel2. Mol. Cell 2014, 54, 119-32.

5.      Rao, F., See, RY., Zhang, D., Toh, DC., Liang Z-X. YybT is a signaling protein that contains a cyclic-di-nucleotide phosphodiesterase domain and a GGDEF domain with ATPase activity. J. Biol. Chem. 2010, 285:473-82.

6.      Tan, E#., Rao, F#., Pasunooti, S., Pham, TH., Soehano, I., Turner, MS., Liew, CW., Lescar, J., Pervushin, K., Liang, Z-X. Solution structure of the PAS domain of a thermophilic YybT homolog reveals a potential ligand-binding site. J. Biol. Chem. 2013, 288:11949-59. (#: Cofirst author).