Structure of the human UBR5 E3 ubiquitin ligase

Wang, Rui; He, Qun; Wen-hu, Zhan; Yu, Ziqi; Finkin-Groner, Efrat; Ma, Xiaojing; Lin, Gang; Li, Huilin

doi:10.1016/j.str.2023.03.010

Cited by 22 publications

(17 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Yet, the mechanism through which UBR5 recognizes Rb is still unclear. UBR5 likely engages its substrates as a dimer or tetramer, which can target distinct degron linear motifs as indicated by recent cryo-EM structures 52,53,[59][60][61] . Since UBR5 is a large multi-domain protein, it is possible that different docking mechanisms can be utilized for engaging different groups of substrates 51,53,[60][61][62] .…”

Section: Discussionmentioning

confidence: 99%

“…UBR5 likely engages its substrates as a dimer or tetramer, which can target distinct degron linear motifs as indicated by recent cryo-EM structures 52,53,[59][60][61] . Since UBR5 is a large multi-domain protein, it is possible that different docking mechanisms can be utilized for engaging different groups of substrates 51,53,[60][61][62] . Interestingly, two recent studies proposed that UBR5 targets its substrates on chromatin 52,53 .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The G1/S transition is promoted by Rb degradation via the E3 ligase UBR5

Zhang,

Valenzuela,

Zatulovskiy

et al. 2023

Preprint

View full text Add to dashboard Cite

Mammalian cells make the decision to divide at the G1/S transition in response to diverse signals impinging on the retinoblastoma protein Rb, a cell cycle inhibitor and tumor suppressor. Rb is inhibited by two parallel pathways. In the canonical pathway, cyclin D-Cdk4/6 kinase complexes phosphorylate and inactivate Rb. In the second, recently discovered pathway, Rb’s concentration decreases during G1 through an unknown mechanism. Here, we found that regulated protein degradation via the E3 ubiquitin ligase UBR5 is responsible for Rb’s concentration drop in G1.UBR5knockout cells have increased Rb concentration in early G1, exhibited a lower G1/S transition rate, and are more sensitive to inhibition of Cdk4/6. This last observation suggests that UBR5 inhibition can strengthen the efficacy of Cdk4/6 inhibitor-based cancer therapies.One-Sentence SummaryThe E3 ligase UBR5 progressively reduces the concentration of the retinoblastoma protein Rb during G1 to drive proliferation.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The G1/S transition is promoted by Rb degradation via the E3 ligase UBR5

Zhang,

Valenzuela,

Zatulovskiy

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…As HECT E3 ligases are often very large, ranging from 700 amino acids to giant enzymes of more than 3000 residues (i.e UBR5, [20] HUWE1 and HERC1, 2798, 4374 and 4861 residues respectively), it can be a challenge to study them in biochemical studies. Strikingly, the isolated C-terminal HECT domain of UBR5, was still able to process UbSRhodol in a catalytic transthiolation dependant manner (Supporting Information Figure 7A).…”

Section: Profiling Transthiolation Activitymentioning

confidence: 99%

A Pro‐Fluorescent Ubiquitin‐Based Probe to Monitor Cysteine‐Based E3 Ligase Activity

Pérez Berrocal,

Vishwanatha,

Horn‐Ghetko

et al. 2023

Angewandte Chemie

View full text Add to dashboard Cite

Protein post-translational modification with ubiquitin (Ub) is a versatile signal regulating almost all aspects of cell biology, and an increasing range of diseases is associated with impaired Ub modification. In this light, the Ub system offers an attractive, yet underexplored route to the development of novel targeted treatments. A promising strategy for small molecule intervention is posed by the final components of the enzymatic ubiquitination cascade, E3 ligases, as they determine the specificity of the protein ubiquitination pathway. Here, we present UbSRhodol, an autoimmolative Ub-based probe, which upon E3 processing liberates the pro-fluorescent dye, amenable to profile the E3 transthiolation activity for recombinant and in cellextract E3 ligases. UbSRhodol enabled detection of changes in transthiolation efficacy evoked by enzyme key point mutations or conformational changes, and offers an excellent assay reagent amenable to a highthroughput screening setup allowing the identification of small molecules modulating E3 activity.

show abstract

“…Met and Leu stimulate ARID1A ubiquitination degradation in bovine MECs through the E3 ubiquitin ligase TRIM21 . The ubiquitin protein ligase E3 module N-recognition 5 (UBR5) is a key regulator in cancer development. , However, the mechanism via which UBR5 exerts its regulatory roles is still not fully defined, and it is yet unknown whether UBR5 can affect ARID1A stability.…”

Section: Introductionmentioning

confidence: 99%

Methionine and Leucine Promote mTOR Gene Transcription and Milk Synthesis in Mammary Epithelial Cells through the eEF1Bα-UBR5-ARID1A Signaling

Qi,

Yu,

Fan

et al. 2024

J. Agric. Food Chem.

View full text Add to dashboard Cite

Amino acids are essential for the activation of the mechanistic target of rapamycin (mTOR), but the corresponding molecular mechanism is not yet fully understood. We previously found that Met stimulated eukaryotic elongation factor α (eEF1Bα) nuclear localization in bovine mammary epithelial cells (MECs). Herein, we explored the role and molecular mechanism of eEF1Bα in methionine (Met)-and leucine (Leu)-stimulated mTOR gene transcription and milk synthesis in MECs. eEF1Bα knockdown decreased milk protein and fat synthesis, cell proliferation, and mTOR mRNA expression and phosphorylation, whereas eEF1Bα overexpression had the opposite effects. QE-MS analysis detected that eEF1Bα was phosphorylated at Ser106 in the nucleus and Met and Leu stimulated p-eEF1Bα nuclear localization. eEF1Bα knockdown abrogated the stimulation of Met and Leu by mTOR mRNA expression and phosphorylation, and this regulatory role was dependent on its phosphorylation. Akt knockdown blocked the stimulation of Met and Leu by eEF1Bα and p-eEF1Bα expression. ChIP-PCR detected that p-eEF1Bα bound only to the −548 to −793 nt site in the mTOR promoter, and ChIP-qPCR further detected that Met and Leu stimulated this binding. eEF1Bα mediated Met and Leu' stimulation on mTOR mRNA expression and phosphorylation through inducing AT-rich interaction domain 1A (ARID1A) ubiquitination degradation, and this process depended on eEF1Bα phosphorylation. p-eEF1Bα interacted with ARID1A and ubiquitin protein ligase E3 module N-recognition 5 (UBR5), and UBR5 knockdown rescued the decrease of the ARID1A protein level by eEF1Bα overexpression. Both eEF1Bα and p-eEF1Bα were highly expressed in mouse mammary gland tissues during the lactating period. In summary, we reveal that Met and Leu stimulate mTOR transcriptional activation and milk protein and fat synthesis in MECs through eEF1Bα-UBR5-ARID1A signaling.

show abstract

Structure of the human UBR5 E3 ubiquitin ligase

Cited by 22 publications

References 85 publications

The G1/S transition is promoted by Rb degradation via the E3 ligase UBR5

The G1/S transition is promoted by Rb degradation via the E3 ligase UBR5

A Pro‐Fluorescent Ubiquitin‐Based Probe to Monitor Cysteine‐Based E3 Ligase Activity

Methionine and Leucine Promote mTOR Gene Transcription and Milk Synthesis in Mammary Epithelial Cells through the eEF1Bα-UBR5-ARID1A Signaling

Contact Info

Product

Resources

About