Abstract
The E3 ligase activity of Cullin RING Ligases (CRLs) is controlled by cycles of neddylation/deneddylation and intimately regulated by the deneddylase COP9 Signalosome (CSN), one of the proteasome lid-CSN-initiation factor 3 (PCI) domain-containing “Zomes” complex. Besides catalyzing the removal of stimulatory Cullin neddylation, CSN also provides a docking platform for other proteins that might play a role in regulating CRLs, notably protein kinases and deubiquitinases. During the CRL activity cycle, CRL–CSN complexes are dynamically assembled and disassembled. Mechanisms underlying complex dynamics remain incompletely understood. Recently, the inositol polyphosphate metabolites (IP6, IP7) and their metabolic enzymes (IP5K, IP6K) have been discovered to participate in CRL–CSN complex formation as well as stimulus-dependent dissociation. Here we discuss these mechanistic insights in light of recent advances in elucidating structural basis of CRL–CSN complexes.
Highlights
The “Zomes” complexes refer to three proteastasis-related machineries with subunits containing the proteasome lid-CSN-initiation factor 3 (PCI) domain and the MPN (Mpr1/Pad1 N-terminal) domain: the translation initiation factor-3, the 19S regulatory subunit of the 26S proteasome, and the COP9 singalosome (CSN)
CSN was first identified and purified from Arabidopsis and named COP9 because mutations in its subunits lead to Constitutive Photomorphogenesis (COP), even when seedlings were grown in the dark [3,4]
The N-terminal portions of CSN2 and CSN4 interact with the RING domain of Rbx1, and the WHB domain of Cullins, conformation rearrangement in this region is consistent with an induced-fit mechanism to strengthen cognate enzyme-substrate recognition; Second, because the CSN5 MPN
Summary
The “Zomes” complexes refer to three proteastasis-related machineries with subunits containing the PCI (proteasome lid-CSN-initiation factor 3) domain and the MPN (Mpr1/Pad N-terminal) domain: the translation initiation factor-3, the 19S regulatory subunit of the 26S proteasome, and the COP9 singalosome (CSN). Complex-independent functions have been reported for certain CSN subunits [11,12,13], the primary biochemical role of CSN is to regulate the Cullin RING ubiquitin ligases (CRLs) as a deneddylase holoenzyme. The E3 ligase activity of CRLs is controlled by reversible Cullin neddylation (modification by the ubiquitin-like protein Nedd8) and deneddylation [15]. Genetic disruption of CSN subunits can lead to constitutive CRL activation and self-destruction, eventually diminishing CRL function [26,27]. This apparent inconsistency, known as the “CSN paradox”, indicates that CSN protects CRL from being aberrantly active under basal condition, while enabling proper CRL dissociation and activation in a signal-dependent manner [28].
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