Institutional News
Dr. Feng Rao's lab identified inositol hexakisphosphate as an intermolecular "glue" mediating the assembly and activity of Cullin E3 ubiquitin ligases .
On Mar. 15, 2016-Dr. Feng Rao's lab, working together with Dr. Sol Snyder’s lab at Johns Hopkins University, elucidated the biochemical mechanism and cellular function of inositol hexakisphosphate (IP6) in mediating dynamic assembly of the Cullin-COP9 signalosome complexes, as well as the E3 ligase activity of Cullins. The work entitled "Inositol hexakisphosphate (IP6) generated by IP5K mediates Cullin-COP9 signalosome interactions and CRL function" is published online in the Journal PNAS.
The Cullin family of E3 ubiquitin ligases mediates the turnover of 20% of the proteome. Cullins ubiquitylate numerous substrates involved in cell growth/death and DNA repair, commending their being emerging anti-tumor targets (Nat Rev Drug Discov 2014 13, 889-). Cullins 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 Cullins. Elucidating the mechanism of binding and dynamic disassembly of the Cullin-CSN complexes is therefore key to understand physiological functions of Cullins.
Here, the authors 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, the authors find that IP5K and IP6 physiologically mediate interactions between CSN2 and Cullins to facilitate the assembly of Cullin-CSN complexes and regulate their downstream functions. Together with earlier studies from these authors, these findings establish that IP6, in conjunction with its metabolizing enzymes, determines the stability, activity and dynamics of Cullin-CSN complexes.
Research Assistants Yan Ding and Zhiqing Liu are the co-first and second authors of this paper. Drs Feng Rao and Sol Snyder are co-corresponding authors. Other authors include Paul Scherer (co-first), Drs Jing Xu and James Barrow from Johns Hopkins University, Drs Haibin Mao and Ning Zheng from Washington University, and Dr. Ning Wei from Yale University. This research was supported in part by the 973 National High-Tech. Projects, and the Beijing Municipal Government.
