Corralling a protein-degradation regulator

Deshaies, Raymond J.

doi:10.1038/nature13644

Cited by 7 publications

(6 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This structure included all eight previously characterized subunits of CSN: six PCI domain‐containing subunits and two MPN domain‐containing subunits. As shown in Figure 3, this deduced CSN structure resembles a “tomato” sitting on the palm (Deshaies 2014; Lingaraju et al 2014). Specifically, the crystal structure of CSN showed that the PCI ring (CSN1–4 and CSN7–8) organizes the helical repeat domains responsible for binding SCF SKP2/CKS1 , while the helical bundle enables CSN5 to sense the assembly state of CSN, favoring its own integration when the complex is otherwise fully assembled (Lingaraju et al 2014).…”

Section: Biochemical Activity and 3d Structure Of Csnmentioning

confidence: 78%

COP9 signalosome: Discovery, conservation, activity, and function

Qin

et al. 2020

JIPB

View full text Add to dashboard Cite

The COP9 signalosome (CSN) is a conserved protein complex, typically composed of eight subunits (designated as CSN1 to CSN8) in higher eukaryotes such as plants and animals, but of fewer subunits in some lower eukaryotes such as yeasts. The CSN complex is originally identified in plants from a genetic screen for mutants that mimic light-induced photomorphogenic development when grown in the dark. The CSN complex regulates the activity of cullin-RING ligase (CRL) families of E3 ubiquitin ligase complexes, and play critical roles in regulating gene expression, cell proliferation, and cell cycle. This review aims to summarize the discovery, composition, structure, and function of CSN in the regulation of plant development in response to external (light and temperature) and internal cues (phytohormones).

show abstract

Section: Biochemical Activity and 3d Structure Of Csnmentioning

confidence: 78%

COP9 signalosome: Discovery, conservation, activity, and function

Qin

et al. 2020

JIPB

View full text Add to dashboard Cite

show abstract

“…Resting on the hand is the box, formed by…the carboxy-terminal ends of each subunit. Sitting atop…is the CSN5–CSN6 tomato….” [35]). The structure also revealed that in the absence of substrate (i.e., CRL) binding, the catalytically active site in CSN5 is auto-inhibited by glutamate residue 104 that blocks the Zn 2+ atom in the active site, which prevents binding of the hydrolytic water molecule.…”

Section: The Cop9 Signalosome: Discovery Structure and Functionsmentioning

confidence: 99%

“…The inactive state is only released upon binding of the NEDDylated CRL substrate, which elicits conformational changes mediated via subunits CSN4 and 6 that eventually lead to the activation of the isopeptidase activity in CSN5 and, therefore, NEDD8 removal from cullins. Thus, the isopeptidase activity of CSN5 within the CSN complex is regulated differently than in other JAMM-containing enzymes such as AMSH-LP and Rpn11 [17,35,36,37].…”

Section: The Cop9 Signalosome: Discovery Structure and Functionsmentioning

confidence: 99%

Role of the COP9 Signalosome (CSN) in Cardiovascular Diseases

2019

View full text Add to dashboard Cite

The constitutive photomorphogenesis 9 (COP9) signalosome (CSN) is an evolutionarily conserved multi-protein complex, consisting of eight subunits termed CSN1-CSN8. The main biochemical function of the CSN is the control of protein degradation via the ubiquitin-proteasome-system through regulation of cullin-RING E3-ligase (CRL) activity by deNEDDylation of cullins, but the CSN also serves as a docking platform for signaling proteins. The catalytic deNEDDylase (isopeptidase) activity of the complex is executed by CSN5, but only efficiently occurs in the three-dimensional architectural context of the complex. Due to its positioning in a central cellular pathway connected to cell responses such as cell-cycle, proliferation, and signaling, the CSN has been implicated in several human diseases, with most evidence available for a role in cancer. However, emerging evidence also suggests that the CSN is involved in inflammation and cardiovascular diseases. This is both due to its role in controlling CRLs, regulating components of key inflammatory pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and complex-independent interactions of subunits such as CSN5 with inflammatory proteins. In this case, we summarize and discuss studies suggesting that the CSN may have a key role in cardiovascular diseases such as atherosclerosis and heart failure. We discuss the implicated molecular mechanisms ranging from inflammatory NF-κB signaling to proteotoxicity and necrosis, covering disease-relevant cell types such as myeloid and endothelial cells or cardiomyocytes. While the CSN is considered to be disease-exacerbating in most cancer entities, the cardiovascular studies suggest potent protective activities in the vasculature and heart. The underlying mechanisms and potential therapeutic avenues will be critically discussed.

show abstract

“…Established MPN + –MPN − domain pairings include CSN5 and CSN6 in the COP9 signalosome and RPN11 and RPN8 in the proteasome. While the mode of MPN + –MPN − interaction is conserved between these two systems ( Deshaies, 2014 ; Lingaraju et al, 2014 ; Pathare et al, 2014 ; Worden et al, 2014 ), no precise function has been ascribed to either MPN − domain, and neither structure has been probed deeply for insights into how the MPN − domain might support MPN + domain function.…”

Section: Introductionmentioning

confidence: 99%

Higher-Order Assembly of BRCC36–KIAA0157 Is Required for DUB Activity and Biological Function

et al. 2015

View full text Add to dashboard Cite

Summary BRCC36 is a Zn2+ dependent deubiquitinating enzyme (DUB) that hydrolyzes lysine-63-linked ubiquitin chains as part of distinct macromolecular complexes that participate in either interferon signaling or DNA-damage recognition. The MPN+ domain protein BRCC36 associates with pseudo-DUB MPN− proteins KIAA0157 or Abraxas, which are essential for BRCC36 enzymatic activity. To understand the basis for BRCC36 regulation, we have solved the structure of an active BRCC36-KIAA0157 heterodimer and an inactive BRCC36 homodimer. Structural and functional characterizations show how BRCC36 is switched to an active conformation by contacts with KIAA0157. Higher order association of BRCC36 and KIAA0157 into a dimer of heterodimers (super dimers) was required for DUB activity and interaction with targeting proteins SHMT2 and RAP80. These data provide the first explanation of how an inactive pseudo DUB allosterically activates a cognate DUB partner, and implicates super dimerization as a new regulatory mechanism underlying BRCC36 DUB activity, subcellular localization, and biological function.

show abstract

Corralling a protein-degradation regulator

Cited by 7 publications

References 17 publications

COP9 signalosome: Discovery, conservation, activity, and function

COP9 signalosome: Discovery, conservation, activity, and function

Role of the COP9 Signalosome (CSN) in Cardiovascular Diseases

Higher-Order Assembly of BRCC36–KIAA0157 Is Required for DUB Activity and Biological Function

Contact Info

Product

Resources

About