The COP9 signalosome: more than a protease

The COP9 signalosome (CSN) is a conserved protein complex that functions in the ubiquitin–proteasome pathway. After two decades of research, we now know that the CSN is a multi-subunit protease that regulates the activity of cullin–RING ligase (CRL) families of ubiquitin E3 complexes. The CSN is rapidly emerging as a key player in the DNA-damage response, cell-cycle control and gene expression. The independent functions of CSN5 (also known as JAB1) add to the complexity of the CSN machinery. Here, we provide an updated view of the structure, functions and regulation of this protein complex. The COP9 signalosome (CSN) is a conserved protein complex that functions in the ubiquitin–proteasome pathway. After two decades of research, we now know that the CSN is a multi-subunit protease that regulates the activity of cullin–RING ligase (CRL) families of ubiquitin E3 complexes. The CSN is rapidly emerging as a key player in the DNA-damage response, cell-cycle control and gene expression. The independent functions of CSN5 (also known as JAB1) add to the complexity of the CSN machinery. Here, we provide an updated view of the structure, functions and regulation of this protein complex. Rad9–Rad1–Hus1 complex. A heterotrimeric protein complex that forms a ‘doughnut-shaped’ sliding clamp around DNA after damage and/or replication fork stalling. cullin-associated and neddylation-dissociated 1. This protein specifically associates with deneddylated cullins to sequester them in an unassembled and inactive state. It was previously named TBP-interacting protein 120A (TIP120A). cullin–RING ligases, a superfamily of ubiquitin ligases. It typically consists of a cullin family member as a molecular scaffold and of a small RING protein, RBX1 (also named ROC1 or HRT1), which forms the core complex. An active CRL is formed when the cullin–RBX1 core is assembled with a substrate-binding module that recruits substrates. There are at least six different cullin proteins in humans, each assembling with a unique substrate-binding module. deneddylase 1 or Nedd8-specific protease 1. A dual function cysteinyl protease capable of processing the Nedd8 C terminus and of deconjugating Nedd8 chains on CUL1. eukaryotic translation initiation factor 3. It is the largest and most complex translation initiation factor, composed of 13 subunits in human. It stimulates assembly of the eIF2–GTP–Met-tRNA ternary complex and the formation of the 43S pre-initiation complex. It also facilitates mRNA recruitment to the 43S complex and mRNA scanning for AUG recognition. global genome repair. A nucleotide-excision repair pathway that scans the entire genome for helix-distorting DNA damage. huntington, elongation factor 3, PR65/A, TOR. A tandemly repeated, 37–47 amino acid long module occurring in several cytoplasmic proteins. Arrays of HEAT repeats consist of 3–36 units forming a rod-like helical structure and seem to function as protein–protein interaction surfaces. JAB1/MPN domain metalloenzyme (or MPN+). It possesses a His-Xaa-His-Xaa10-Asp motif (in which Xaa represents any residue) accompanied by an upstream conserved Glu residue. The activity requires a zinc metal ion. The JAMM motif is found in the CSN5 subunit of the CSN, the RPN11 subunit of the proteasome and the C6.1A protein. MPR1–PAD1–N-terminal domain. This domain is defined by sequence homology found in subunits of the proteasome, eIF3 and the CSN. It is usually located at the N-terminal half of a protein. Nedd8 (neural precursor cell-expressed developmentally downregulated-8) is used in metazoans, whereas RUB1 (related to ubiquitin 1) is used in yeast and plants. It is an ubiquitin-like protein that can be covalently conjugated to a cullin protein through a process termed neddylation. The enzymatic steps of neddylation are similar to ubiquitylation, but are catalyzed by Nedd8-specific set of E1, E2 and E3 enzymes. Recently, other neddylation targets, apart from cullins, have been reported. proteasome–COP9 signalosome–initiation factor 3 domain (or proteasome subunits, Int- 6, Nip-1 and TRIP-15) domain. Like MPN, this domain is also defined by sequence homology from subunits of the proteasome, eIF3 and the CSN. It is usually located in the C-terminal region of a protein. SKP1–cullin–F-box complex. It is a type of CRL ubiquitin ligase that contains a SKP1 adaptor protein, CUL1–RBX1 and an F-box-containing substrate receptor, which confers substrate specificity. transcription coupled repair. A nucleotide-excision repair pathway that preferentially removes lesions from the coding strands of genes actively transcribed by RNA polymerase II. tetratrico peptide repeat domain. A 34 amino acid sequence repeat, clusters of which fold into a helical structure and mediate protein–protein interactions.