NEDD8 and ubiquitin ligation by cullin-RING E3 ligases

Baek, Kheewoong; Scott, Daniel C.; Schulman, Brenda A.

doi:10.1016/j.sbi.2020.10.007

Cited by 101 publications

(83 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CRLs assemble and perform ubiquitylation when opposite ends of a CUL-RBX core scaffold associate with interchangeable substrate-bound receptors and catalytic UB-carrying enzymes 4 , 13 . Suites of substrate-binding receptors—often in complex with adapter proteins—associate with cognate cullin N-terminal domains 4 .…”

Section: Mainmentioning

confidence: 99%

CUL5-ARIH2 E3-E3 ubiquitin ligase structure reveals cullin-specific NEDD8 activation

et al. 2021

Self Cite

View full text Add to dashboard Cite

An emerging mechanism of ubiquitylation involves partnering of two distinct E3 ligases. In the best-characterized E3-E3 pathways, ARIH-family RING-between-RING (RBR) E3s ligate ubiquitin to substrates of neddylated cullin-RING E3s. The E3 ARIH2 has been implicated in ubiquitylation of substrates of neddylated CUL5-RBX2-based E3s, including APOBEC3-family substrates of the host E3 hijacked by HIV-1 virion infectivity factor (Vif). However, the structural mechanisms remained elusive. Here structural and biochemical analyses reveal distinctive ARIH2 autoinhibition, and activation on assembly with neddylated CUL5-RBX2. Comparison to structures of E3-E3 assemblies comprising ARIH1 and neddylated CUL1-RBX1-based E3s shows cullin-specific regulation by NEDD8. Whereas CUL1-linked NEDD8 directly recruits ARIH1, CUL5-linked NEDD8 does not bind ARIH2. Instead, the data reveal an allosteric mechanism. NEDD8 uniquely contacts covalently linked CUL5, and elicits structural rearrangements that unveil cryptic ARIH2-binding sites. The data reveal how a ubiquitin-like protein induces protein-protein interactions indirectly, through allostery. Allosteric specificity of ubiquitin-like protein modifications may offer opportunities for therapeutic targeting.

show abstract

Section: Mainmentioning

confidence: 99%

CUL5-ARIH2 E3-E3 ubiquitin ligase structure reveals cullin-specific NEDD8 activation

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…RBX1 and RBX2 interact with the E2 ligases, UBC12 and UBE2F, respectively, in order to conjugate NEDD8 to members of the Cullin-RING ligase (CRL) family [22,23]. The CRLs are a group of ubiquitin ligases that require the addition of a C-terminal NEDD8 modification in order to become activated [24][25][26]. The constitutive photomorphogenesis 9 (COP9) signalosome is a protein complex capable of interacting with NEDDylated CRLs and removing the NEDD8 modification, thereby reversing the activity of the NEDDylation cascade and acting as an "off" switch to the Cullins [27].…”

Section: Neddylation As a Therapeutic Targetmentioning

confidence: 99%

Targeting NEDDylation as a Novel Approach to Improve the Treatment of Head and Neck Cancer

Jones

Carew

Bauman

et al. 2021

Cancers

View full text Add to dashboard Cite

Head and neck cancer is diagnosed in nearly 900,000 new patients worldwide each year. Despite this alarming number, patient outcomes, particularly for those diagnosed with late-stage and human papillomavirus (HPV)-negative disease, have only marginally improved in the last three decades. New therapeutics that target novel pathways are desperately needed. NEDDylation is a key cellular process by which NEDD8 proteins are conjugated to substrate proteins in order to modulate their function. NEDDylation is closely tied to appropriate protein degradation, particularly proteins involved in cell cycle regulation, DNA damage repair, and cellular stress response. Components of the NEDDylation pathway are frequently overexpressed or hyperactivated in many cancer types including head and neck cancer, which contribute to disease progression and drug resistance. Therefore, targeting NEDDylation could have a major impact for malignancies with alterations in the pathway, and this has already been demonstrated in preclinical studies and clinical trials. Here, we will survey the mechanisms by which aberrant NEDDylation contributes to disease pathogenesis and discuss the potential clinical implications of inhibiting NEDDylation as a novel approach for the treatment of head and neck cancer.

show abstract

“…Cullins are modified by NEDD8 on a conserved lysine in the C-terminus (Rabut & Peter, 2008). NEDD8 stimulates CRL recruitment of E2 or partner E3 and blocks its binding from the native CRL inhibitor CAND1 (Cullin-associated NEDD8-dissociated 1) (Baek et al, 2020a(Baek et al, , 2020bDuda et al, 2008;Schwechheimer, 2018;Wu et al, 2013), thereby activating CRLs. The treatment of MLN4924 can lead to the deneddylation of CRLs and the accumulation of CRL substrates, many of which are involved in DDR (e.g., CDT1, p27 and p21) Hannss & Dubiel, 2011).…”

Section: Crl Neddylation and Dna Damage Responsementioning

confidence: 99%

Role of NEDD8 and neddylation dynamics in DNA damage response

Luo

Rao

2021

GENOME INSTAB. DIS.

View full text Add to dashboard Cite

Every single cell in human body is suffering ~ 7000 DNA lesions of various types every day. Different kinds of DNA damage response (DDR) are evolved to overcome these threats to maintain genome stability. Failure in the DDR system leads to various diseases ranging from cancer to neurodevelopmental defects. Past years' studies have unraveled the close relationship between neddylation, an ubiquitin-like modification, and DDR. This functional interplay involves the neddylation of Cullin RING E3 ligases, the prototype neddylation substrates, and non-Cullin-based neddylation targets, both of which have intimate links to DDR. More recently, unconjugated NEDD8 polymers are implicated in DDR as well. Here we summarize these findings to better understand the role that neddylation and deneddylation plays in DDR.

show abstract

NEDD8 and ubiquitin ligation by cullin-RING E3 ligases

Cited by 101 publications

References 50 publications

CUL5-ARIH2 E3-E3 ubiquitin ligase structure reveals cullin-specific NEDD8 activation

CUL5-ARIH2 E3-E3 ubiquitin ligase structure reveals cullin-specific NEDD8 activation

Targeting NEDDylation as a Novel Approach to Improve the Treatment of Head and Neck Cancer

Role of NEDD8 and neddylation dynamics in DNA damage response

Contact Info

Product

Resources

About