Structural Biology of CRL Ubiquitin Ligases

Rusnac, Domniţa-Valeria; Zheng, Ning

doi:10.1007/978-981-15-1025-0_2

Cited by 44 publications

(38 citation statements)

References 89 publications

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“…Much like well-studied multiprotein E3 ligases, such as anaphase-promoting complex/cyclosome (APC/C) or cullin-RING ligases, GID is not a singular complex—a core catalytic and scaffolding assembly is modulated by other subunits ( Barford, 2020 ; Karayel et al., 2020 ; Liu and Pfirrmann, 2019 ; Melnykov et al., 2019 ; Qiao et al., 2020 ; Rusnac and Zheng, 2020 ; Watson et al., 2019 ). The constituents of various GID assemblies and how they achieve regulation are beginning to emerge.…”

Section: Introductionmentioning

confidence: 99%

GID E3 ligase supramolecular chelate assembly configures multipronged ubiquitin targeting of an oligomeric metabolic enzyme

Sherpa¹,

Chrustowicz²,

Qiao³

et al. 2021

Molecular Cell

115

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Summary How are E3 ubiquitin ligases configured to match substrate quaternary structures? Here, by studying the yeast GID complex (mutation of which causes deficiency in glucose-induced degradation of gluconeogenic enzymes), we discover supramolecular chelate assembly as an E3 ligase strategy for targeting an oligomeric substrate. Cryoelectron microscopy (cryo-EM) structures show that, to bind the tetrameric substrate fructose-1,6-bisphosphatase (Fbp1), two minimally functional GID E3s assemble into the 20-protein Chelator-GID SR4 , which resembles an organometallic supramolecular chelate. The Chelator-GID SR4 assembly avidly binds multiple Fbp1 degrons so that multiple Fbp1 protomers are simultaneously ubiquitylated at lysines near the allosteric and substrate binding sites. Importantly, key structural and biochemical features, including capacity for supramolecular assembly, are preserved in the human ortholog, the CTLH E3. Based on our integrative structural, biochemical, and cell biological data, we propose that higher-order E3 ligase assembly generally enables multipronged targeting, capable of simultaneously incapacitating multiple protomers and functionalities of oligomeric substrates.

show abstract

Section: Introductionmentioning

confidence: 99%

GID E3 ligase supramolecular chelate assembly configures multipronged ubiquitin targeting of an oligomeric metabolic enzyme

Sherpa¹,

Chrustowicz²,

Qiao³

et al. 2021

Molecular Cell

115

View full text Add to dashboard Cite

show abstract

“…Much like well-studied multiprotein E3 ligases such as Anaphase-Promoting Complex/Cyclosome or Cullin-RING ligases, GID is not a singular complex (Barford, 2020;Liu and Pfirrmann, 2019;Melnykov et al, 2019;Qiao et al, 2020;Rusnac and Zheng, 2020;Watson et al, 2019). The constituents of various GID assemblies, and how they achieve regulation is beginning to emerge.…”

Section: Introductionmentioning

confidence: 99%

GID E3 ligase supramolecular chelate assembly configures multipronged ubiquitin targeting of an oligomeric metabolic enzyme

Sherpa¹,

Chrustowicz²,

Qiao³

et al. 2021

Preprint

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To achieve precise cellular regulation, E3 ubiquitin ligases must be configured to match substrate quaternary structures. Here, by studying the yeast GID complex, mutation of which is Glucose-Induced Degradation deficient, we discover supramolecular chelate assembly as an E3 ligase strategy for targeting an oligomeric substrate. Cryo EM structures show that to bind the tetrameric substrate fructose-1,6-bisphosphatase (Fbp1), two otherwise functional GID E3s assemble into a 20-protein Chelator-GIDSR4, which resembles an organometallic supramolecular chelate. The Chelator-GIDSR4 assembly avidly binds multiple Fbp1 degrons and positions Fbp1 so that its protomers are simultaneously ubiquitylated at lysines near its allosteric and substrate binding sites. Significantly, key structural and biochemical features - including capacity for supramolecular assembly - are preserved in the human ortholog, the CTLH E3. Based on our integrative structural, biochemical and cell biological data, we propose that higher-order E3 ligase assembly generally underlies multipronged targeting, capable of simultaneously incapacitating multiple protomers and functionalities of oligomeric substrates.

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“…CRLs are classified based on the type of cullin subunit (Cul1, Cul2, Cul3, Cul4A, Cul4B, Cul5 and Cul7) [10]. Structures of fully assembled CRL complexes have highlighted a range of conformations and orientations attained by the different cullin subunits [11].…”

Section: Structural Assembly and Activity Of Modular Multi-subunit E3 Ligasesmentioning

confidence: 99%

“…CRLs employ a substrate receptor module to provide specificity for substrate recognition [10,11,22]. This section focuses on recent advances in the understanding of the structural basis of the highly diverse substrate recognition by E3 CRLs.…”

Section: Substrate Recognition By E3 Ligase Substrate Receptorsmentioning

confidence: 99%

Building ubiquitination machineries: E3 ligase multi-subunit assembly and substrate targeting by PROTACs and molecular glues

Ramachandran

Ciulli

2021

Current Opinion in Structural Biology

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Structural Biology of CRL Ubiquitin Ligases

Cited by 44 publications

References 89 publications

GID E3 ligase supramolecular chelate assembly configures multipronged ubiquitin targeting of an oligomeric metabolic enzyme

GID E3 ligase supramolecular chelate assembly configures multipronged ubiquitin targeting of an oligomeric metabolic enzyme

GID E3 ligase supramolecular chelate assembly configures multipronged ubiquitin targeting of an oligomeric metabolic enzyme

Building ubiquitination machineries: E3 ligase multi-subunit assembly and substrate targeting by PROTACs and molecular glues

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