6A73

Complex structure of CSN2 with IP6

Summary for 6A73

• Entry DOI: 10.2210/pdb6a73/pdb
• Descriptor: COP9 signalosome complex subunit 2,Endolysin, INOSITOL HEXAKISPHOSPHATE, SULFATE ION, ... (4 entities in total)
• Functional Keywords: subunit2 of cop9 signalosome (csn)., signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 72142.96

Authors

Liu, L.,Li, D.,Rao, F.,Wang, T. (deposition date: 2018-07-02, release date: 2019-07-03, Last modification date: 2023-11-22)

Primary citation

Lin, H.,Zhang, X.,Liu, L.,Fu, Q.,Zang, C.,Ding, Y.,Su, Y.,Xu, Z.,He, S.,Yang, X.,Wei, X.,Mao, H.,Cui, Y.,Wei, Y.,Zhou, C.,Du, L.,Huang, N.,Zheng, N.,Wang, T.,Rao, F.
Basis for metabolite-dependent Cullin-RING ligase deneddylation by the COP9 signalosome.
Proc.Natl.Acad.Sci.USA, 117:4117-4124, 2020

PubMed Abstract: 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) as a general CSN cofactor recruiting CRLs. We determined the crystal structure of IP in complex with CSN subunit 2 (CSN2), based on which we identified the IP-corresponding electron density in the cryoelectron microscopy map of a CRL4A-CSN complex. IP 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 binding-deficient knockin mice are embryonic lethal. The same mutation disabled Csn2 from rescuing UV-hypersensitivity of -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 small molecule, whose metabolism may be coupled to CRL-CSN complex dynamics.

PubMed: 32047038
DOI: 10.1073/pnas.1911998117

Experimental method

X-RAY DIFFRACTION (2.447 Å)