Insights into Cullin-RING E3 Ubiquitin Ligase Recruitment: Structure of the VHL-EloBC-Cul2 Complex

Nguyen, Henry C.; Yang, Haitao; Fribourgh, Jennifer L.; Wolfe, Leslie S.; Xiong, Yong

doi:10.1016/j.str.2014.12.014

Cited by 64 publications

(93 citation statements)

References 61 publications

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“…5h). These findings were corroborated by computational molecular docking whereby a N-terminally-derived ID2 peptide (amino acids 15-31) docked preferentially to a groove on the molecular surface of VHL:Elongin C 22 with the N-terminal half of its interaction surface contacting the SOCS box of VHL that binds Cul2 (primarily K159) and the C-terminal half (including T27) fitting snugly into a hydrophobic pocket mostly contributed by the Elongin C surface (Extended Data Fig. 6a, c, d).…”

Section: Id2 Binds and Disrupts The Vcb-cul2 Complexmentioning

confidence: 72%

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An ID2-dependent mechanism for VHL inactivation in cancer

Lee

Frattini

Bansal

et al. 2016

Nature

111

127

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Mechanisms that maintain cancer stem cells are crucial to tumor progression. The ID2 protein underpins cancer hallmarks including the cancer stem cell state. HIFα transcription factors, most notably HIF2α, are expressed in and required for maintenance of cancer stem cells (CSCs). However, the pathways that are engaged by ID2 or drive HIF2α accumulation in CSCs have remained unclear. We report that DYRK1A and DYRK1B kinases phosphorylate ID2 on Threonine-27 (T27). Hypoxia down regulates this phosphorylation via inactivation of DYRK1, whose activity is stimulated in normoxia by the oxygen sensing prolyl hydroxylase PHD1. ID2 binds to the VHL ubiquitin ligase complex, displaces VHL-associated Cullin-2, and impairs HIF2α ubiquitylation and degradation. Phosphorylation of ID2-T27 by DYRK1 blocks ID2-VHL interaction and preserves HIF2α ubiquitylation. In glioblastoma ID2 positively modulates HIF2α activity. Conversely, elevated expression of DYRK1 phosphorylates ID2- T27, leading to HIF2α destabilization, loss of glioma stemness, inhibition of tumor growth, and a more favorable outcome for patients with glioblastoma.

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Section: Id2 Binds and Disrupts The Vcb-cul2 Complexmentioning

confidence: 72%

“…4d, e). Interestingly, mutation of lysine 159 (K159E), which provides the VHL contact surface for binding to Cul2 21,22 , impaired the interaction with ID2 (Fig. 4e).…”

Section: Id2 Binds and Disrupts The Vcb-cul2 Complexmentioning

confidence: 99%

An ID2-dependent mechanism for VHL inactivation in cancer

Lee

Frattini

Bansal

et al. 2016

Nature

111

127

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“…2 The former has 213 amino acids and consists of 3 domains (N-terminal, b-sheet and C-terminal domains). 6,7 In our study, we found 2 point mutations in the VHL gene, specifically c.256C > T (p.P86S) and c.340 C 5G > C, both of which were considered pathogenic mutations in the past. 2,18 However, the c.340 C 5G > C mutation, which was associated with VHL type 1B disease, 2,18 has always been disputed because some researchers suggest that it is a benign polymorphism.…”

Section: Discussionmentioning

confidence: 58%

“…6,7 Its b-sheet domain contains a small hydrophobic core composed of F76, P86, Y98, P99, L101, W117 and F119, and mutations in this region were reported to dramatically impair VHL function, such as F119S. 6,8 P86 is located in the center of the hydrophobic core, and its mutation to the hydrophilic residue serine may severely destabilize the hydrophobic core and lead to VHL dysfunction (Fig.…”

Section: Structure Modeling Of the Mutant Proteinmentioning

confidence: 99%

Germline mutations in theVHLgene associated with 3 different renal lesions in a Chinese von Hippel-Lindau disease family

Yuan

Sun

Hao

et al. 2016

Cancer Biology & Therapy

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Von Hippel-Lindau (VHL) disease is a rare autosomal dominant inherited cancer syndrome that is characterized by hemangioblastomas in the central nervous system and retina, renal cell carcinoma and cysts, pancreatic tumors and cysts, and pheochromocytoma. The underlying gene in this disease is the VHL tumor suppressor gene. We characterized a family with 2 affected siblings. The brother and sister displayed VHL type 2B and type 2A features, respectively. Renal lesions in the brother exhibited 3 different phenotypes, including simple renal cysts, multilocular cystic renal cell carcinoma and clear cell renal cell carcinoma. The phenotypes of the 3 concurrent renal lesions were first reported in this study. Mutation detection of the VHL gene revealed 2 recurrent mutations, namely c.256C>T (p.P86S) and c.340 C 5G > C. The former was predicted to be deleterious and to destabilize the hydrophobic core and lead to VHL dysfunction; however, the latter was predicted to be a benign variant. Our findings provided new data for the genotype-phenotype of VHL diseases and elucidated the pathogenic mechanism with in silico analysis.

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“…Members of CRLs function in a wide range of dynamic cellular processes, including the cell cycle, signal transduction, and transcription. And CRLs exhibit a conserved overall architecture that has plasticity to fine-tune the specific recruitment of different cullins [20]. …”

Section: Introductionmentioning

confidence: 99%

Atlas on substrate recognition subunits of CRL2 E3 ligases

et al. 2016

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The Cullin2-type ubiquitin ligases belong to the Cullin-Ring Ligase (CRL) family, which is a crucial determinant of proteasome-based degradation processes in eukaryotes. Because of the finding of von Hippel-Lindau tumor suppressor (VHL), the Cullin2-type ubiquitin ligases gain focusing in the research of many diseases, especially in tumors. These multisubunit enzymes are composed of the Ring finger protein, the Cullin2 scaffold protein, the Elongin B&C linker protein and the variant substrate recognition subunits (SRSs), among which the Cullin2 scaffold protein is the determining factor of the enzyme mechanism. Substrate recognition of Cullin2-type ubiquitin ligases depends on SRSs and results in the degradation of diseases associated substrates by intracellular signaling events. This review focuses on the diversity and the multifunctionality of SRSs in the Cullin2-type ubiquitin ligases, including VHL, LRR-1, FEM1b, PRAME and ZYG11. Recently, as more SRSs are being discovered and more aspects of substrate recognition have been illuminated, insight into the relationship between Cul2-dependent SRSs and substrates provides a new area for cancer research.

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Insights into Cullin-RING E3 Ubiquitin Ligase Recruitment: Structure of the VHL-EloBC-Cul2 Complex

Cited by 64 publications

References 61 publications

An ID2-dependent mechanism for VHL inactivation in cancer

An ID2-dependent mechanism for VHL inactivation in cancer

Germline mutations in theVHLgene associated with 3 different renal lesions in a Chinese von Hippel-Lindau disease family

Atlas on substrate recognition subunits of CRL2 E3 ligases

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