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NEDD8 nucleates a multivalent cullin–RING–UBE2D ubiquitin ligation assembly
Open accessAbstract
Eukaryotic cell biology depends on cullin-RING E3 ligase (CRL)-catalysed protein ubiquitylation 1, which is tightly controlled by the modification of cullin with the ubiquitin-like protein NEDD8 2-6. However, how CRLs catalyse ubiquitylation, and the basis of NEDD8 activation, remain unknown. Here we report the cryo-electron microscopy structure of a chemically trapped complex that represents the ubiquitylation intermediate, in which the neddylated CRL1 β-TRCP promotes the transfer of ubiquitin from the E2 ubiquitin-conjugating enzyme UBE2D to its recruited substrate, phosphorylated IκBα. NEDD8 acts as a nexus that binds disparate cullin elements and the RING-activated ubiquitin-linked UBE2D. Local structural remodelling of NEDD8 and large-scale movements of CRL domains converge to juxtapose the substrate and the ubiquitylation active site. These findings explain how a distinctive ubiquitin-like protein alters the functions of its targets, and show how numerous NEDD8-dependent interprotein interactions and conformational changes synergistically configure a catalytic CRL architecture that is both robust, to enable rapid ubiquitylation of the substrate, and fragile, to enable the subsequent functions of cullin-RING proteins.
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TL;DR
The paper reports a 3.7 Å cryo-EM structure of a chemically trapped neddylated CRL1β-TRCP–UBE2D~UB–IκBα substrate intermediate, showing NEDD8 as a nexus that organizes activation, catalytic, and substrate-scaffolding modules. NEDD8-dependent multivalent interactions and conformational changes explain nearly 2000-fold stimulation of substrate priming and why NEDD8, rather than ubiquitin, activates CRLs.
Key findings
- NEDD8 massively stimulates CRL1β-TRCP/UBE2D-catalyzed ubiquitylation by nearly 2000-fold overall; for IκBα, K_m for UBE2D was 408 ± 57 nM with neddylated CRL1β-TRCP versus 4014 ± 956 nM unneddylated, and k_obs S0–S1 was 12.9 ± 1.7 s⁻¹ versus 0.05 ± 0.002 s⁻¹, a 2667-fold change (Extended Data Table 1). NEDD8 activates both substrate priming and chain elongation, but UB linkage to a substrate-linked UB is 10-fold slower, suggesting optimal catalysis of substrate priming.
- The 3.7 Å structure of the trapped neddylated CRL1β-TRCP–UBE2D~UB–substrate intermediate shows NEDD8 nearly encircled by interactions, binding its linked CUL1 WHB domain in an “activation module” and positioning a “catalytic module” relative to the substrate-scaffolding module; RBX1 binds UBE2D~UB in the canonical RING-activated closed conformation, and the structurally observed distance between IκBα’s β-TRCP-bound phosphodegron and the UBE2D~UB active site is ≈22 Å.
- NEDD8 must adopt the Loop-out conformation to both form the activation module and engage UBE2D in the catalytic module, acting as a coincidence detector; mutations disrupting activation-module, activation–catalytic, or activation–substrate-scaffolding interfaces impair substrate priming, and combining mutations is synergistic (e.g., NEDD8 I44A is ≈10-fold defective alone, but with UBE2D H32A is nearly 200-fold defective).
- The same mutations impair UBE2D-mediated priming with neddylated CRL1FBW7 and neddylated CRL4CRBN/pomalidomide, and the structure rationalizes how NEDD8 Gln40 deamidation by bacterial effectors impairs CRL1-dependent ubiquitylation.
Methods
- Cryo-EM: a chemically adjoined stable proxy for the UBE2D~UB–IκBα substrate intermediate was bound to a hyperactive neddylated CRL1β-TRCP; the final reconstruction was refined globally to 3.7 Å (focused refinement 3.46 Å), with model building/refinement using known PDB structures, RELION-3.0, COOT, and Phenix.refine.
- Kinetics: rapid quench-flow pre-steady-state experiments and UBE2D titrations with radiolabeled peptide substrates (IκBα and β-catenin variants) estimated K_m and k_obs; pulse-chase fluorescent assays monitored substrate priming, and separate assays monitored intrinsic UBE2D~UB discharge to free lysine.
- Samples: human recombinant proteins were expressed in insect cells or E. coli, including UBE2D2/3, RBX1, CUL1, CUL4, NEDD8, UB, SKP1, β-TRCP, CRBN, DDB1, and UBA1; peptides were >95% HPLC purity, and variants were generated by PCR, Quikchange, or synthesis.
Limitations
- Stated: the authors cannot exclude that UB could be transferred from RING- and NEDD8-bound UBE2D in various orientations relative to the substrate-scaffolding module; different forms of ubiquitylation may involve alternative, presently elusive catalytic architectures; and the structural basis for ubiquitylation by other CRLs awaits future studies.
- Evident: the structure relies on a chemically trapped proxy, a hyperactive RBX1 N98R mutant, monomeric β-TRCP1, SKP1∆∆, and engineered UBE2D variants, so it may not capture all native transient conformations or wild-type dynamics.
- Evident: the biochemical assays are in vitro with model peptide substrates, some validation assays are qualitative, and several experiments report n = 2 technical replicates rather than independent biological replicates.
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63 Own result · 41 Not checked yet · 29 Own interpretation · 6 Own method · 3 No basis given · 1 Supported so far
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In the paper
“UB transfer from a RING-docked UBE2D~UB intermediate (“~” indicates thioester bond/thioester-bond mimic) to an F-box protein-bound substrate is difficult to rationalize by prior structural models 3,7,20,27, or by our cryo EM reconstructions of unneddylated and neddylated substrate-bound CRL1β-TRCP”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Cryo EM reveals Cullin-RING dynamics
What the sources say
- Supportedcites [3] Duda, D. M. et al. Structural insights into NEDD8 activation of cullin–RING ligases: conformational control of conjugation. Cell 134, 995–1006 (2008). source
The Introduction says that docking a ubiquitin E2 to Rbx1 in prior CRL structural models leaves an approximately 60 Å gap between the E2 catalytic site and the substrate-binding site, raising the question of how ubiquitin reaches the target. This supports the cited point about the difficulty posed by prior models; the citing authors attribute the cryo-EM reconstructions to their own work, not to this source. (LLM, conf=0.90)
- Not checked yetcites [7] Zheng, N. et al. Structure of the Cul1–Rbx1–Skp1–F boxSkp2 SCF ubiquitin ligase complex. Nature 416, 703–709 (2002). source
- Not checked yetcites [20] Wu, G. et al. Structure of a β-TrCP1–Skp1–β-catenin complex: destruction motif binding and lysine specificity of the SCFβ-TrCP1 ubiquitin ligase. Mol. Cell 11, 1445–1456 (2003). source
- Not checked yetcites [27] Tang, X. et al. Suprafacial orientation of the SCFCdc4 dimer accommodates multiple geometries for substrate ubiquitination. Cell 129, 1165–1176 (2007). source
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In the paper
“A well-resolved “substrate scaffolding module” resembles models based on crystal structures of substrate-bound SKP1-β-TRCP and the portion of an F-box-SKP1-CUL1-RBX1 complex including CUL1’s N-terminal domain and the intermolecular C/R domain7,20.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Cryo EM reveals Cullin-RING dynamics
What the sources say
- Not checked yetcites [7] Zheng, N. et al. Structure of the Cul1–Rbx1–Skp1–F boxSkp2 SCF ubiquitin ligase complex. Nature 416, 703–709 (2002). source
- Not checked yetcites [20] Wu, G. et al. Structure of a β-TrCP1–Skp1–β-catenin complex: destruction motif binding and lysine specificity of the SCFβ-TrCP1 ubiquitin ligase. Mol. Cell 11, 1445–1456 (2003). source
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In the paper
“we obtained a reconstruction at 3.7 Å resolution showing our proxy for a UBE2D~UB-IκBα substrate intermediate bound to a hyperactive version of neddylated CRL1β-TRCP”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Capturing CRL substrate ubiquitylation
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In the paper
“Concomitant local structural remodeling and large-scale CRL domain movements converge to juxtapose the substrate and ubiquitylation active site.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Abstract
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In the paper
“We chemically adjoined surrogates for these entities in a stable mimic of the transition state, which avidly binds neddylated CRL1β-TRCP”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Capturing CRL substrate ubiquitylation
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In the paper
“The structurally-observed ≈22 angstroms between IκBα’s β-TRCP-bound phosphodegron and the UBE2D~UB active site is compatible with spacing between this motif and potential acceptor lysines in many substrates32”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Capturing CRL substrate ubiquitylation
What the sources say
- Not checked yetcites [32] Low, T. Y. et al. A systems-wide screen identifies substrates of the SCFβTrCP ubiquitin ligase. Sci. Signal. 7, rs8 (2014).
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In the paper
“Kinetic parameters for CRL1β-TRCP and UBE2D-catalyzed ubiquitylation of model substrates (phosphopeptides from β-catenin and IκBα, harboring single acceptor lysines), determined by rapid quench-flow methods, showed NEDD8 massively stimulates the reaction, by nearly 2000-fold overall”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > NEDD8 activation of ubiquitylation
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In the paper
“We report the cryo EM structure of a chemically-trapped complex representing the ubiquitylation intermediate whereby neddylated CRL1β-TRCP promotes UB transfer from the E2 UBE2D to its recruited substrate phosphorylated IκBα.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Abstract
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In the paper
“The structure shows that NEDD8 acts as a nexus binding disparate cullin elements and the RING-activated UB-linked UBE2D.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Abstract
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In the paper
“Compared to prior isolated RING-UBE2D~UB structures28–30, the neddylated CRL1β-TRCP-UBE2D~UB-substrate intermediate shows additional density corresponding to the substrate proxy along a trajectory to the ubiquitylation active site”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Capturing CRL substrate ubiquitylation
What the sources say
- Not checked yetcites [28] Dou, H., Buetow, L., Sibbet, G. J., Cameron, K. & Huang, D. T. BIRC7–E2 ubiquitin conjugate structure reveals the mechanism of ubiquitin transfer by a RING dimer. Nat. Struct. Mol. Biol. 19, 876–883 (2012). source
- Not checked yetcites [29] Plechanovová, A., Jaffray, E. G., Tatham, M. H., Naismith, J. H. & Hay, R. T. Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis. Nature 489, 115–120 (2012). source
- Not checked yetcites [30] Pruneda, J. N. et al. Structure of an E3:E2~Ub complex reveals an allosteric mechanism shared among RING/U-box ligases. Mol. Cell 47, 933–942 (2012). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 32
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In the paper
“In the catalytic module, RBX1 binds UBE2D~UB in the canonical RING-activated “closed” conformation, where noncovalent UBE2D and UB interactions allosterically activate the thioester bond between them28–30.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Capturing CRL substrate ubiquitylation
What the sources say
- Not checked yetcites [28] Dou, H., Buetow, L., Sibbet, G. J., Cameron, K. & Huang, D. T. BIRC7–E2 ubiquitin conjugate structure reveals the mechanism of ubiquitin transfer by a RING dimer. Nat. Struct. Mol. Biol. 19, 876–883 (2012). source
- Not checked yetcites [29] Plechanovová, A., Jaffray, E. G., Tatham, M. H., Naismith, J. H. & Hay, R. T. Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis. Nature 489, 115–120 (2012). source
- Not checked yetcites [30] Pruneda, J. N. et al. Structure of an E3:E2~Ub complex reveals an allosteric mechanism shared among RING/U-box ligases. Mol. Cell 47, 933–942 (2012). source
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In the paper
“Comparing kinetic parameters for peptide substrates with 13-, 9-, and 4-residue spacers confirms these predictions, with the latter peptide reducing the priming rate with neddylated CRL1β-TRCP to below that we could quantify”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Capturing CRL substrate ubiquitylation
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In the paper
“NEDD8 is nearly encircled by interactions, binding its linked CUL1 WHB domain in an “activation module”, and positioning a “catalytic module” relative to the substrate scaffolding module to juxtapose the active site and substrate”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Capturing CRL substrate ubiquitylation
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In the paper
“However, 10-fold slower UB linkage to a substrate-linked UB suggests neddylated CRL1β-TRCP together with UBE2D optimally catalyzes substrate priming”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > NEDD8 activation of ubiquitylation
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In the paper
“Quantifying individual rates for linkage of successive UBs during polyubiquitylation showed NEDD8 activates both reactions.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > NEDD8 activation of ubiquitylation
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In the paper
“its linked NEDD8 (encircled in yellow) is bound to the backside of UBE2D, but the donor UB (absent from region circled in orange) was not visible”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
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In the paper
“Contacts resemble those described for free NEDD8 or UB binding to UBE2D’s backside, and allosterically stimulating intrinsic reactivity of an isolated RING-UBE2D~UB subcomplex35–38.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > NEDD8 orchestrates UB ligation assembly
What the sources say
- Not checked yetcites [35] Ozkan, E., Yu, H. & Deisenhofer, J. Mechanistic insight into the allosteric activation of a ubiquitin-conjugating enzyme by RING-type ubiquitin ligases. Proc. Natl Acad. Sci. USA 102, 18890–18895 (2005). source
- Not checked yetcites [36] Brzovic, P. S., Lissounov, A., Christensen, D. E., Hoyt, D. W. & Klevit, R. E. A. A UbcH5/ubiquitin noncovalent complex is required for processive BRCA1-directed ubiquitination. Mol. Cell 21, 873–880 (2006). source
- Not checked yetcites [37] Sakata, E. et al. Direct interactions between NEDD8 and ubiquitin E2 conjugating enzymes upregulate cullin-based E3 ligase activity. Nat. Struct. Mol. Biol. 14, 167–168 (2007). source
- Not checked yetcites [38] Buetow, L. et al. Activation of a primed RING E3-E2–ubiquitin complex by non-covalent ubiquitin. Mol. Cell 58, 297–310 (2015). source
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In the paper
“NEDD8’s Leu2, Lys4, Glu14, Asp16, Arg25, Arg29, Glu32, Gly63 and Gly64, which nestle in a concave CUL1 surface, vary in UB and account for nearly one-third of sequence differences between them”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > NEDD8 orchestrates UB ligation assembly
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In the paper
“the mutations also impair UBE2D-mediated priming of a Cyclin E phosphopeptide substrate with neddylated CRL1FBW7, and of IKZF zinc finger 2 by neddylated CRL4CRBN/Pomalidomide”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Synergistic catalytic assembly
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“First, although no individual mutation is as detrimental as eliminating neddylation, mutation of each interface has a roughly 10-fold or greater effect on its own.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Synergistic catalytic assembly
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In the paper
“Our data show NEDD8 must adopt the Loop-out conformation to both form the activation module and to engage UBE2D in the catalytic module”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > NEDD8 conformation coincidence coupling
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In the paper
“Mutations designed to destroy the activation module (NEDD8 Q40E) or hinder interactions between the activation and catalytic modules (NEDD8 I44A or UBE2D S22R) substantially impair substrate priming, as does swapping key NEDD8 residues at the interface with the substrate scaffolding module with those in UB.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Synergistic catalytic assembly
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- Rests on an assumption: Mutations designed to destroy the activation module or hinder interactions between the activation and catalytic modules actually disrupt those intended interfaces.
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In the paper
“Substrate-independent UB transferase activity was impaired by a NEDD8 mutant disrupting the integrity of the activation module, and by UBE2D mutations hindering interactions with its covalently-linked UB, RBX1’s RING domain or NEDD8”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > NEDD8 orchestrates UB ligation assembly
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In the paper
“In the absence of other factors, neddylated CRL1β-TRCP’s scaffolding module robustly bridges the substrate with the C/R domain, while NEDD8, it’s linked CUL1 WHB and RBX1’s RING domain are relatively dynamic, apparently waving around”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Discussion
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In the paper
“| WT β-cat | WT UBE2D | CUL1–RBX1 | 4638±138 | 0.05 ± 0.005 | - | 1.1 x 104 | 2000 |”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
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In the paper
“First, the dimer exacerbated structural heterogeneity, with minor differences presumably based on natural motions between the two protomers.”
- Also stated in: § Extended Data · plain
“Variations between the two protomers of the dimer also exacerbated sample heterogeneity.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Early attempt to visualize UB transfer by neddylated CRL1β-TRCP and UBE2D and rationale for approaches to improve EM samples
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- Also stated in: § Extended Data · plain
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In the paper
“final reconstruction refined to 3.7Å resolution shown on right”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
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In the paper
“| IκBα | WT UBE2D | NEDD8-CUL1–RBX1 | 408 ± 57 | 12.9 ± 1.7 | 0.24 ± 0.04 | 3.2 x 107 | - |”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
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In the paper
“The phoshpo-IκBα peptide-substrate-bound β-TRCP-SKP1-CUL1-RBX1-NEDD8-UBE2D portion of this map superimposes with the map for the dimeric complex shown in e, but here the entire complex is visible, including both the NEDD8 (encircled in yellow) and donor UB (encircled in orange).”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
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In the paper
“NEDD8, encircled in yellow, is the entity displaying the highest local resolution in the map.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
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In the paper
“showing the effect of UBE2D H32A mutation at the interface between the catalytic and substrate scaffolding modules.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
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- Rests on an assumption: The UBE2D H32A mutation is at the interface between the catalytic and substrate scaffolding modules.
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In the paper
“| WT β-cat | WT UBE2D | NEDD8-CUL1–RBX1 | 214 ±30 | 4.8 ±0.46 | 0.19 ±0.02 | 2.2 x 107 | - |”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
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In the paper
“wherein the dimerization domain agrees well with the prior crystal structure27”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
What the sources say
- Not checked yetcites [27] Tang, X. et al. Suprafacial orientation of the SCFCdc4 dimer accommodates multiple geometries for substrate ubiquitination. Cell 129, 1165–1176 (2007). source
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In the paper
“| medium β-cat | WT UBE2D | NEDD8-CUL1–RBX1 | 372 ± 48 | 11 ±1.00 | 0.24 ± 0.04 | 3.0 x 107 | - |”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
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In the paper
“Ultimately, reconstruction of the data yielded a focused refinement at 3.46 Å resolution and a global refinement at 3.7 Å resolution that superimposes well with lower resolution maps obtained during attempts to visualize substrate priming with neddylated wild-type dimeric CRL1β-TRCP.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
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In the paper
““short” β-catenin peptide with a lysine 5 residues upstream of the N-terminal phosphoSer in the degron”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
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In the paper
“| medium β-cat | S22R UBE2D | NEDD8-CUL1–RBX1 | 913±135 | 1.89 ±0.14 | 0.17 ±0.03 | 2.1 x 106 | 14.2 |”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
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In the paper
“| medium β-cat | WT UBE2D | NEDD8 I44A-CUL1–RBX1 | 1087 ±69 | 3.60 ±0.27 | 0.17 ±0.03 | 3.3 x 106 | 9.1 |”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
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In the paper
“| medium β-cat | H32A UBE2D | NEDD8-CUL1–RBX1 | 347 ± 53 | 8.15 ± 1.04 | 0.73 ± 0.09 | 2.3 x 107 | 1.3 |”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
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In the paper
“| medium β-cat | WT UBE2D | UBylized NEDD8-CUL1–RBX1 | 1651±137 | 2.20 ±0.15 | 0.17 ±0.04 | 1.3 x 106 | 23.1 |”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
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In the paper
“| medium β-cat | WT UBE2D | NEDD8 Q40E-CUL1–RBX1 | 1941 ±226 | 1.77 ± 0.13 | 0.07 ±0.01 | 9.1 x 105 | 33 |”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
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In the paper
“| medium β-cat | WT UBE2D | UB-CUL1–RBX1 | 2056 ±170 | 1.0 ±0.03 | 0.15 ±0.01 | 4.9 x 105 | 61.2 |”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“show how numerous NEDD8-dependent interprotein interactions and conformational changes synergistically configure a catalytic CRL architecture that is both robust for rapid substrate ubiquitylation and fragile to enable ensuing cullin-RING functions.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Abstract
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In the paper
“NEDD8 Gln40 deamidation by an enteropathogenic and enterohemorrhagic Escherichia coli effector results in accumulation of the CRL1β-TRCP substrate IκBα as well as substrates of other CRLs24–26.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Abstract
What the sources say
- Not checked yetcites [24] Cui, J. et al. Glutamine deamidation and dysfunction of ubiquitin/NEDD8 induced by a bacterial effector family. Science 329, 1215–1218 (2010). source
- Not checked yetcites [25] Jubelin, G. et al. Pathogenic bacteria target NEDD8-conjugated cullins to hijack host-cell signaling pathways. PLoS Pathog. 6, e1001128 (2010). source
- Not checked yetcites [26] Morikawa, H. et al. The bacterial effector Cif interferes with SCF ubiquitin ligase function by inhibiting deneddylation of Cullin1. Biochem. Biophys. Res. Commun. 401, 268–274 (2010). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“hijacking of CRL1β-TRCP enables HIV to evade host immunity23”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Abstract
What the sources say
- Not checked yetcites [23] Margottin, F. et al. A novel human WD protein, h-βTrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif. Mol. Cell 1, 565–574 (1998). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“mutations impairing CRL1β-TRCP ubiquitylation of β-catenin promote tumorigenesis22.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Abstract
What the sources say
- Not checked yetcites [22] Frescas, D. & Pagano, M. Deregulated proteolysis by the F-box proteins SKP2 and β-TrCP: tipping the scales of cancer. Nat. Rev. Cancer 8, 438–449 (2008). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Because ubiquitylation does occur with mutant substrates or enzymes, albeit at substantially lower rates (Extended Data Table 1), we cannot exclude that UB could be transferred from RING- and NEDD8-bound UBE2D in various orientations relative to the substrate-scaffolding module.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Discussion
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In the paper
“Our assay for CRL4CRBN ubiquitylation of IKZF was established based on findings that ZF2 mediates tight immunomodulatory-drug dependent interaction sufficient to target degradation, UBE2D3 contributes to stability of CRL4CRBN neomorphic substrates in cells57,60,61.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Other biochemical assays > Substrate priming assays
What the sources say
- Not checked yetcites [57] Koduri, V. et al. Peptidic degron for IMiD-induced degradation of heterologous proteins. Proc. Natl Acad. Sci. USA 116, 2539–2544 (2019). source
- Not checked yetcites [60] Sievers, Q. L. et al. Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science 362 eaat0572 (2018). source
- Not checked yetcites [61] Lu, G. et al. UBE2G1 governs the destruction of cereblon neomorphic substrates. eLife 7, e40958 (2018). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Their UB counterparts would be predicted to repel CUL1, rationalizing a need for NEDD8 as a distinctive UB-like protein.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > NEDD8 orchestrates UB ligation assembly
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In the paper
“The numerous requisite protein-protein interactions and conformational changes suggest there could be multiple routes to the catalytic architecture (Figure 4b), where formation of interfaces successively narrows the range of options, akin to progression down a free energy funnel.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Discussion
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In the paper
“Our assay for CRL4CRBN ubiquitylation of IKZF was established based on findings that ZF2 mediates tight immunomodulatory-drug dependent interaction sufficient to target degradation, UBE2D3 contributes to stability of CRL4CRBN neomorphic substrates in cells57,60,61.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Other biochemical assays > Substrate priming assays
What the sources say
- Not checked yetcites [57] Koduri, V. et al. Peptidic degron for IMiD-induced degradation of heterologous proteins. Proc. Natl Acad. Sci. USA 116, 2539–2544 (2019). source
- Not checked yetcites [60] Sievers, Q. L. et al. Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science 362 eaat0572 (2018). source
- Not checked yetcites [61] Lu, G. et al. UBE2G1 governs the destruction of cereblon neomorphic substrates. eLife 7, e40958 (2018). source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
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In the paper
“Second, perplexing neddylated CRL features incompatible with prior structures are now rationalized, including NEDD8-stimulated crosslinking between a CRL1β-TRCP-bound phosphopeptide and UBE2D4; simultaneous NEDD8 linkage to a cullin and binding to the backside of RBX1-bound UBE2D3,7,37; and catastrophic effects of bacterial effector-catalyzed NEDD8 Gln40 deamidation24–26”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Discussion
What the sources say
- Not checked yetcites [4] Saha, A. & Deshaies, R. J. Multimodal activation of the ubiquitin ligase SCF by Nedd8 conjugation. Mol. Cell 32, 21–31 (2008). source
- Not checked yetcites [3] Duda, D. M. et al. Structural insights into NEDD8 activation of cullin–RING ligases: conformational control of conjugation. Cell 134, 995–1006 (2008). source
- Not checked yetcites [7] Zheng, N. et al. Structure of the Cul1–Rbx1–Skp1–F boxSkp2 SCF ubiquitin ligase complex. Nature 416, 703–709 (2002). source
- Not checked yetcites [37] Sakata, E. et al. Direct interactions between NEDD8 and ubiquitin E2 conjugating enzymes upregulate cullin-based E3 ligase activity. Nat. Struct. Mol. Biol. 14, 167–168 (2007). source
- Not checked yetcites [24] Cui, J. et al. Glutamine deamidation and dysfunction of ubiquitin/NEDD8 induced by a bacterial effector family. Science 329, 1215–1218 (2010). source
- Not checked yetcites [25] Jubelin, G. et al. Pathogenic bacteria target NEDD8-conjugated cullins to hijack host-cell signaling pathways. PLoS Pathog. 6, e1001128 (2010). source
- Not checked yetcites [26] Morikawa, H. et al. The bacterial effector Cif interferes with SCF ubiquitin ligase function by inhibiting deneddylation of Cullin1. Biochem. Biophys. Res. Commun. 401, 268–274 (2010). source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, the architecture observed in the neddylated CRL1β-TRCP-UBE2D~UB-substrate complex structure may both stimulate intrinsic reactivity of the UBE2D~UB intermediate and place the catalytic center in proximity of the β-TRCP-bound substrate.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > NEDD8 orchestrates UB ligation assembly
hedgedconditional- Asserted: passes — The authors put it forward as true.
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Ubiquitylation of IκBα by CRL1β-TRCP via UBE2D3 was monitored using a pulse-chase format that specifically detects CRLβ-TRCP-dependent UB modification from UBE2D to IκBα independently of effects on UBA1-dependent formation of the UBE23D~UB intermediate.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Other biochemical assays > Substrate priming assays
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While neddylated CRL1β-TRCP and UBE2D seem optimal for UB priming of peptide-like substrates, the limited effect of the mutations on linkage of subsequent UBs (Extended Data Table 1) raises the possibility that different forms of ubiquitylation involve alternative, presently elusive, catalytic architectures.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“used the RBX1 N98R variant that is hyperactive toward UBE2D~UB39.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Other biochemical assays > Assays for intrinsic activation of UBE2D~UB intermediate
What the sources say
- Not checked yetcites [39] Scott, D. C. et al. Structure of a RING E3 trapped in action reveals ligation mechanism for the ubiquitin-like protein NEDD8. Cell 157, 1671–1684 (2014). source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“This rationalizes how pathogenic bacterial effectors catalyzing Gln40 deamidation impair CRL1-dependent ubiquitylation12,24–26: the resultant negative charge would shatter the CUL1-NEDD8 interface.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > NEDD8 orchestrates UB ligation assembly
What the sources say
- Not checked yetcites [12] Yu, C. et al. Gln40 deamidation blocks structural reconfiguration and activation of SCF ubiquitin ligase complex by Nedd8. Nat. Commun. 6, 10053 (2015).
- Not checked yetcites [24] Cui, J. et al. Glutamine deamidation and dysfunction of ubiquitin/NEDD8 induced by a bacterial effector family. Science 329, 1215–1218 (2010). source
- Not checked yetcites [25] Jubelin, G. et al. Pathogenic bacteria target NEDD8-conjugated cullins to hijack host-cell signaling pathways. PLoS Pathog. 6, e1001128 (2010). source
- Not checked yetcites [26] Morikawa, H. et al. The bacterial effector Cif interferes with SCF ubiquitin ligase function by inhibiting deneddylation of Cullin1. Biochem. Biophys. Res. Commun. 401, 268–274 (2010). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The activation module binds the catalytic module, solving the mystery of how neddylation helps CRL1β-TRCP recruit UBE2D in cells34.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > NEDD8 orchestrates UB ligation assembly
What the sources say
- Not checked yetcites [34] Kawakami, T. et al. NEDD8 recruits E2-ubiquitin to SCF E3 ligase. EMBO J. 20, 4003–4012 (2001). source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“in the unneddylated versions the NEDD8 modification sites of CUL1 and CUL4 were mutated to Arg (CUL1 K720R and CUL4A K705R) to prevent obscuring interpretation of the results by low-level ubiquitylation of the NEDD8 consensus Lys during the ubiquitylation reactions3.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Other biochemical assays
What the sources say
- Not checked yetcites [3] Duda, D. M. et al. Structural insights into NEDD8 activation of cullin–RING ligases: conformational control of conjugation. Cell 134, 995–1006 (2008). source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“The malleability of neddylated CRLs, coupled with numerous UB carrying enzyme partners, may underlie successful molecular glue or PROTAC-targeted protein degradation, while potential limits in their multivalent catalytic architectures may explain failures in such chemically-directed ubiquitylation of heterologous substrates45.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Discussion
What the sources say
- Not checked yetcites [45] Schapira, M., Calabrese, M. F., Bullock, A. N. & Crews, C. M. Targeted protein degradation: expanding the toolbox. Nat. Rev. Drug Discov. 18, 949–963 (2019). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The worst “single” mutation is NEDD8 substitution with UB (R72A), confirming the importance of NEDD8 and interactions between the activation and substrate scaffolding modules.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Synergistic catalytic assembly
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Third, the mutations have comparatively little effect on chain extension, consistent with the neddylated CRL1β-TRCP-UBE2D~UB-substrate intermediate structure defining UB transfer from UBE2D directly to unmodified substrate.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Synergistic catalytic assembly
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“in an attenuated pulse-chase assay format that qualitatively, but exclusively, monitors NEDD8-activated substrate priming by CRL1β-TRCP and UBE2D”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Synergistic catalytic assembly
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“where aromatic side-chains guide the lysine targets (blue and green, respectively)39,73.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
What the sources say
- Not checked yetcites [39] Scott, D. C. et al. Structure of a RING E3 trapped in action reveals ligation mechanism for the ubiquitin-like protein NEDD8. Cell 157, 1671–1684 (2014). source
- Not checked yetcites [73] Yunus, A. A. & Lima, C. D. Lysine activation and functional analysis of E2-mediated conjugation in the SUMO pathway. Nat. Struct. Mol. Biol. 13, 491–499 (2006). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“we considered that the RBX1 RING sequence represents a compromise to meet requirements for its many different catalytic activities achieved with neddylation E2s, various UB carrying enzymes, and regulators including the inhibitor GLMN72.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
What the sources say
- Not checked yetcites [72] Duda, D. M. et al. Structure of a glomulin–RBX1–CUL1 complex: inhibition of a RING E3 ligase through masking of its E2-binding surface. Mol. Cell 47, 371–382 (2012). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Further iterative manual model building and real space refinements were carried out until good geometry and map to model correlation was reached.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Cryo-EM > Protein identification and model building
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Only a “loop out” conformation is compatible for the CUL1-linked NEDD8 to bind the catalytic module, because “loop in” conformations in the structures shown in g would prevent noncovalent interactions with the UBE2D backside (cyan).”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“CRL1β-TRCP RBX1 RING and CUL1 WHB domains, without or with a covalently-linked NEDD8, are dynamic in the absence of other factors and are harnessed in catalytic architecture for substrate ubiquitylation with UBE2D.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The final reconstructions displayed clear main chain and side chain densities, that enabled us to model and refine the atomic coordinates.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Cryo-EM > Protein identification and model building
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim. It may state two separate claims as one.
In the paper
“whereas in prior cullin crystals this forms the rod-like Helix-29 continuing into the WHB domain7.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
What the sources say
- Not checked yetcites [7] Zheng, N. et al. Structure of the Cul1–Rbx1–Skp1–F boxSkp2 SCF ubiquitin ligase complex. Nature 416, 703–709 (2002). source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“we mutationally introduced a second RBX1 linchpin residue (N98R) previously shown to improve neddylated CRL and UBE2D-dependent substrate priming at the expense of other RBX1-dependent functions (e.g. with UBE2M and UBE2R2)39.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
What the sources say
- Not checked yetcites [39] Scott, D. C. et al. Structure of a RING E3 trapped in action reveals ligation mechanism for the ubiquitin-like protein NEDD8. Cell 157, 1671–1684 (2014). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“using a point mutant version of RBX1 that is hyperactive for substrate priming with UBE2D but defective for UB chain elongation with UBE2R-family E2s39.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Early attempt to visualize UB transfer by neddylated CRL1β-TRCP and UBE2D and rationale for approaches to improve EM samples
What the sources say
- Not checked yetcites [39] Scott, D. C. et al. Structure of a RING E3 trapped in action reveals ligation mechanism for the ubiquitin-like protein NEDD8. Cell 157, 1671–1684 (2014). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Gel images are representative of independent technical replicates (n=2); The symbols from graphs show the data from independent experiments (n = 2)”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
plainn = 2- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Only a “loop out” conformation is compatible with the neddylated CRL activation module structure, because “loop in” conformation from the structures shown in g would prevent noncovalent interactions with CUL1 WHB domain (green).”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Based on the structural locations of these cysteines, we presumed that their mutation hindered formation of the RING-activated, closed, active UBE2D~UB conformation28–30.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
What the sources say
- Not checked yetcites [28] Dou, H., Buetow, L., Sibbet, G. J., Cameron, K. & Huang, D. T. BIRC7–E2 ubiquitin conjugate structure reveals the mechanism of ubiquitin transfer by a RING dimer. Nat. Struct. Mol. Biol. 19, 876–883 (2012). source
- Not checked yetcites [29] Plechanovová, A., Jaffray, E. G., Tatham, M. H., Naismith, J. H. & Hay, R. T. Structure of a RING E3 ligase and ubiquitin-loaded E2 primed for catalysis. Nature 489, 115–120 (2012). source
- Not checked yetcites [30] Pruneda, J. N. et al. Structure of an E3:E2~Ub complex reveals an allosteric mechanism shared among RING/U-box ligases. Mol. Cell 47, 933–942 (2012). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“RBX1’s Trp35 is highlighted to show it serving as a multifunctional platform for either the RING domain in different orientations, or for the E2-linked NEDD8 during neddylation39.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
What the sources say
- Not checked yetcites [39] Scott, D. C. et al. Structure of a RING E3 trapped in action reveals ligation mechanism for the ubiquitin-like protein NEDD8. Cell 157, 1671–1684 (2014). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Gold standard Fourier Shell Correlation curve showing overall resolution at 3.72Å at FSC=0.143.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“removing two loops in SKP1 that are known to be flexible and not required for ubiquitylation activity (although they are required for CAND1-mediated substrate-receptor exchange)13,54”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Early attempt to visualize UB transfer by neddylated CRL1β-TRCP and UBE2D and rationale for approaches to improve EM samples
What the sources say
- Not checked yetcites [13] Pierce, N. W. et al. Cand1 promotes assembly of new SCF complexes through dynamic exchange of F box proteins. Cell 153, 206–215 (2013). source
- Not checked yetcites [54] Schulman, B. A. et al. Insights into SCF ubiquitin ligases from the structure of the Skp1–Skp2 complex. Nature 408, 381–386 (2000). source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
The paper relies on this without support.
Substrate priming involves fleeting simultaneous linkage of UBE2D’s active site, UB’s C-terminus, and the substrate.
“Substrate priming involves fleeting simultaneous linkage of UBE2D’s active site, UB’s C-terminus, and the substrate”
The authors state this as an assumption.
The chemically adjoined surrogate complex is a stable mimic of the transition state and represents the ubiquitylation intermediate.
“We chemically adjoined surrogates for these entities in a stable mimic of the transition state, which avidly binds neddylated CRL1β-TRCP”
The paper relies on this without support.
Mutations designed to destroy the activation module or hinder interactions between the activation and catalytic modules actually disrupt those intended interfaces.
“Mutations designed to destroy the activation module (NEDD8 Q40E) or hinder interactions between the activation and catalytic modules (NEDD8 I44A or UBE2D S22R) substantially impair substrate priming”
The paper relies on this without support.
UBE2D contains three additional cysteines (Cys21, Cys107, Cys111) besides the active-site cysteine.
“However, UBE2D contains three additional cysteines (Cys21, Cys107, Cys111).”
The paper relies on this without support.
UBE2D’s myriad substrates neither conform to a specific motif, nor do they or UBE2D display specific side-chains guiding lysine acceptors into the catalytic center.
“However, UBE2D’s myriad substrates neither conform to a specific motif, nor do they or UBE2D display specific side-chains guiding lysine acceptors into the catalytic center.”
The paper relies on this without support.
The NEDD8 Q40E mutation disrupts the activation module.
“testing effect of NEDD8 Q40E, which would disrupt the activation module.”
The paper relies on this without support.
The NEDD8 I44A mutation disrupts interactions between the activation and catalytic modules.
“showing the effect on substrate priming of disrupting interactions between the activation and catalytic modules with NEDD8 I44A or UBE2D S22R mutation.”
The paper relies on this without support.
The UBE2D S22R mutation disrupts interactions between the activation and catalytic modules.
“showing the effect on substrate priming of disrupting interactions between the activation and catalytic modules with NEDD8 I44A or UBE2D S22R mutation.”
The paper relies on this without support.
The “Ubiquitylized” NEDD8 mutant with six residues swapped for UB counterparts (L2Q K4F E14T D16E G63K G64E) disrupts interactions between the activation and substrate scaffolding modules.
“showing the effect on substrate priming of disrupting interactions between the activation and substrate scaffolding modules, though CUL1 modification by a “Ubiquitylized” NEDD8 mutant with six residues swapped for UB counterparts (L2Q K4F E14T D16E G63K G64E).”
The paper relies on this without support.
The UBE2D H32A mutation is at the interface between the catalytic and substrate scaffolding modules.
“showing the effect of UBE2D H32A mutation at the interface between the catalytic and substrate scaffolding modules.”
The authors state this as an assumption.
The covalently-linked chemical trap is a proxy for the IκBα substrate’s acceptor in the active site.
“highlighting the covalently-linked proxy for the IκBα substrate’s acceptor in the active site”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“ubiquitin E3 ligases serve as scaffolds between a target protein and an activated ubiquitin E2 conjugating enzyme charged with a ubiquitin molecule (E2–Ub), by binding both molecules, then catalysing the transfer of ubiquitin from the active site cysteine of the E2 onto a lysine side chain of a target protein104–107.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [106]
In the citing paper
“The exact mechanism of ubiquitylation for MRLs is not as well understood as the mechanism for CRLs, for which substrate recruitment by multiple adaptors and the molecular details of Ub transfer from E2–Ub to the target has been extensively characterized at the atomic level of an entire CRL1 complex106,117.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [106]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Cryo-EM > Electron microscopy
“For each sample, around 800 images were recorded at 1.997Å/pixel with a nominal magnification of 73,000x.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
“| Magnification | 105,000 | 92,000 | 73,000 | 73,000 | 130,000 | 36,000 | 22,000 |”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Cryo-EM > Electron microscopy
“9112 images were recorded at 1.06Å/pixel with a nominal magnification of 130,000x. A total dose of 70.2 e-/Å2 were fractionated over 60 frames, with a defocus range of -1.2μm to -3.6μm.”
§ NEDD8 nucleates a multivalent cullin-RING-UBE2D ubiquitin ligation assembly > Extended Data
“| Defocus range (μm) | -1.2 ~ -3.6 | -1.5 ~ -3.5 | -1.5 ~ -3.5 | -1.5 ~ -3.5 | -1.2 ~ -3.3 | -1.2 ~ -3.3 | -1.2 ~ -3.3 |”
Citations
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Activity-based profiling of cullin-RING ligase networks by conformation-specific probesPreprint
Henneberg, L. T., Singh, J., Duda, D. M., Baek, K., Yanishevski, D., Murray, P. J., Mann, M., Sidhu, S. S., & Schulman, B. A. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.01.14.524048 · Cited by 2
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Shi, Q., Deng, Z., Zhang, L., Tong, Z., Li, J., Chu, G., Ai, H., & Liu, L. (2024) · Angewandte Chemie · doi:10.1002/ange.202413651 · Cited by 1
Computational approaches to aid PROTAC drug discovery
Chakraborti, S., & McAulay, K. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-29808-0.00004-2 · Cited by 1
HIV proviral transcription and infectivity are enhanced by neddylation
Vaca, C. C., Hudson, H., Clerc, I., Song, C., & D’Aquila, R. T. (2025) · Journal of Virology · doi:10.1128/jvi.00968-25 · Cited by 1
Andree, G. A., Stier, L. J., Schmiederer, K., Thielen, A. S., Schmid, L., Maiwald, S. A., Gottemukkala, K. V., Du, J., von Gronau, S., Strasser, C., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-72524-3 · Cited by 1
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Wang, S., Zhao, S., Wu, J., Du, M., Ma, J., Mo, K., Pang, S., Xu, L., Lei, T., He, Y., et al. (2026) · Plant Cell & Environment · doi:10.1111/pce.70366 · Cited by 1
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Tipping the balance: synthesis and evaluation of centrinone-based degraders of polo-like kinase 4
Kovačević, A., Salim, A., Borges, C., Meraldi, P., & Hoogendoorn, S. (2026) · RSC Chemical Biology · doi:10.1039/d5cb00315f · Cited by 1
Application of chemical protein synthesis in the study of protein ubiquitination
Wu, S., Liang, J., Wu, X., Deng, Z., & Liu, L. (2024) · Scientia Sinica Chimica · doi:10.1360/ssc-2024-0225 · Cited by 2
E3 Ubiquitin Ligases as Molecular Machines and Platforms for Drug Development
Ioris, R. M., Ferris, K., & D’Angiolella, V. (2022) · Wiley eBooks · doi:10.1002/9783527836208.ch3 · Cited by 1
WITHDRAWN: Targeted protein degradation: A promising approach for cancer treatment
Khan, M. Z. I., Nazli, A., Naz, I., Khan, D., Haq, I., & Chen, J. (2023) · Journal of Pharmaceutical Analysis · doi:10.1016/j.jpha.2023.09.004 · Cited by 1
RetractedDET1 dynamics underlie co-operative ubiquitination by CRL4 DET1 -COP1 complexesPreprint
Burgess, A. E., Loughran, T. A., Turk, L. S., Dunlop, J. L., Jamieson, S. A., Curry, J. R., Filipčík, P., Brown, S. H. J., & Mace, P. D. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.06.08.598067 · Cited by 1
Singh, K., Harasimov, K., Niakan, K. K., & Carter, A. P. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.22.713481 · Cited by 1
E3-mediated Ubiquitin and Ubiquitin-like Protein Ligation: Mechanisms and Chemical Probes
Krist, D. T., & Schulman, B. A. (2020) · Royal Society of Chemistry eBooks · doi:10.1039/9781839160691-00184
Self-citationSCF Fbxw5 targets MCAK in G 2 /M to facilitate ciliogenesis in the following cell cyclePreprint
Schweiggert, J., Habeck, G., Hess, S., Mikus, F., Meese, K., Hata, S., Knobeloch, K., & Melchior, F. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.01.15.426831
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A tissue-specific ubiquitin switch coordinates brain, craniofacial, and skin developmentPreprint
Asmar, A. J., Yazejian, R. M., Wu, Y., Collins, J. C., Hsin, J., Cho, J., Doyle, A. D., Cinthala, S., Simon, M., van Jaarsveld, R. H., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.09.26.509591
An In vitro Assay to Recapitulate Hormone-Triggered and SCF-Mediated Protein Ubiquitylation
Niemeyer, M., Parra, J. O. F., & Villalobos, L. I. A. C. (2022) · Methods in molecular biology · doi:10.1007/978-1-0716-2784-6_4
Chen, M., Yan, B., Huang, Y., Wang, C., & Zhang, L. (2023) · PubMed Central · doi:10.13201/j.issn.2096-7993.2023.11.008
Structural basis of dual BACH1 regulation by SCF FBXO22 and SCF FBXL17Preprint
Goretzki, B., Khoshouei, M., Penner, P., Stephan, C., Argoti, D., Dierlamm, N., Rada, J. M., Kapps, S., Thiel, Z., Mutlu, M., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.06.03.596960
Design of linked-domain protein inhibitors of UBE2D as tools to study cellular ubiquitinationPreprint
Bukhari, Z., Gu, L., Nederstigt, A. E., Cope, L. J., Bolhuis, D. L., Harvey, K., Allen, T., Hill, S., Yang, Y., Lawson, G., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.02.610852
Self-citationE3 Siah ubiquitin ligase regulates dichotomous spermatogenesis in Sitotroga cerealella
Shah, S., Shi, C., Elgizawy, K. K., Yan, W.-H., Wu, G., Wang, X., & Yang, F. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1507725
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Mechanistic Insights Into the Assembly of Functional CRL3 Dimeric Complexes
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Expression and purification of functional recombinant Cullin1-Rbx1/2 in E. coli
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The Mechanism of Histone Ubiquitylation by the ASB9-CUL5 Ubiquitin Ligase
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SUMOylation and NEDDylation in kidney diseases
Chen, Z., Li, D., Zhang, J., Wei, B.-Y., Zhao, H., Li, P., & Chen, D. (2025) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2025.105010
Linked-domain inhibitors designed to block UBE2D induce the unfolded protein response
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Self-citationSteric Gating Dictates Selective Activation of BIRC6 by UBA6 Over UBA1Preprint
Tong, Z., Yuan, R., Wu, X., Cai, H., Ziyu, X., Liu, L., & Ai, H. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.03.691989
Evolution, composition and functions of cullin E3 ubiquitin ligases in trypanosomes
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Additional file 1 of Mechanical stress shapes the cancer cell response to neddylation inhibition
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E2 variants for probing E3 ubiquitin ligase activities
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Self-citationCircDCAF6 promotes myoblast differentiation by inhibiting the ubiquitination of ACTC1
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Structural Studies of βTrCP Reveal Plasticity in Binding Modes of Consensus and Nonconsensus Degrons
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Mapping the genetic landscape of HNF1B-dependent cell growth
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Self-citationMolecular Functions of Ubiquitin-like Modifiers in Bacterial Infection
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NAE inhibitor MLN4924 effectively suppresses Coxsackievirus B3 replication
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A Noncanonical Protein Degradation Pathway That Regulates Germ Cell Maintenance
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Design and Semisynthesis of Ubiquitin Extension Probes
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Inhibition of cellular NEDDylation partially alters the MHC class I immunopeptidome
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Metadata
- Authors
- Baek, K., Krist, D. T., Prabu, J. R., Hill, S., Klügel, M., Neumaier, L.-M., von Gronau, S., Kleiger, G., & Schulman, B. A.
- Affiliations
- Max Planck Institute of Biochemistry (DE)
- University of Illinois Urbana-Champaign (US)
- University of Nevada, Las Vegas (US)
- Corresponding author
- Schulman, Brenda A.
- Venue
- Nature
- Published
- 2020-02-12
- Volume
- 578
- Issue
- 7795
- Pages
- 461-466
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7050210
- OpenAlex
- W3006502081
- Cited by
- 270
- References
- 77
- Citations by year
- 2026: 33 · 2025: 33 · 2024: 49 · 2023: 42 · 2022: 39 · 2021: 46 · 2020: 27
- FWCI
- 12.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- National Institute of General Medical Sciences (R15GM117555)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Keywords
- NEDD8, Cullin-RING E3 ligases, ubiquitin transfer, ubiquitination, neddylation, protein ubiquitylation, IκBα, cryo-EM structure, protein-protein interaction, conformational change, E2 ubiquitin-conjugating enzyme
- MeSH terms
- NF-KappaB Inhibitor alpha, NEDD8 Protein, Humans, Models, Molecular, Phosphorylation, Protein Conformation, Substrate Specificity, Cryoelectron Microscopy, Ubiquitin, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Ubiquitination, Biocatalysis
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