부산대학교 도서관

The Cullin-RING ligases (CRLs) are the largest family of ubiquitin E3s activated by neddylation and regulated by the deneddylase COP9 signalosome (CSN). The inositol polyphosphate metabolites promote the formation of CRL-CSN complexes, but with unclear mechanism of action. Here, we provide structural and genetic evidence supporting inositol hexakisphosphate ([IP.sub.6]) as a general CSN cofactor recruiting CRLs. We determined the crystal structure of [IP.sub.6] in complex with CSN subunit 2 (CSN2), based on which we identified the [IP.sub.6]-corresponding electron density in the cryoelectron microscopy map of a CRL4A-CSN complex. [IP.sub.6] binds to a cognate pocket formed by conserved lysine residues from CSN2 and Rbx1/Roc1, thereby strengthening CRL-CSN interactions to dislodge the E2 CDC34/UBE2R from CRL and to promote CRL deneddylation. [IP.sub.6] binding-deficient Csn[2.sup.K70E/K70E] knockin mice are embryonic lethal. The same mutation disabled Schizosaccharomyces pombe Csn2 from rescuing UV-hypersensitivity of csn2-null yeast. These data suggest that CRL transition from the E2-bound active state to the CSN-bound sequestered state is critically assisted by an interfacial [IP.sub.6] small molecule, whose metabolism may be coupled to CRL-CSN complex dynamics. Cullin-RING ligases | deneddylation | COP9 signalosome | inositol hexakisphosphate | intermolecular glue