Affinage

CUL1

Cullin-1 · UniProt Q13616

Length
776 aa
Mass
89.7 kDa
Annotated
2026-06-09
77 papers in source corpus 41 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CUL1 is the central scaffold of the SCF (Skp1-CUL1-F-box) E3 ubiquitin ligase, a modular machine that drives ubiquitin-dependent proteolysis of cell-cycle and signaling regulators (PMID:11961546, PMID:9636170). Structurally, CUL1 is an elongated molecule whose N-terminal helical stalk binds Skp1 and, through it, F-box substrate-recognition proteins such as Skp2 and β-TrCP, while its C-terminal globular domain heterodimerizes with the RING protein RBX1/ROC1 to form a rigid two-subunit catalytic core that positions the substrate over 100 Å from the E2-charged ubiquitin and supports ubiquitin polymerization with the E2 CDC34 (PMID:11961546, PMID:10230406, PMID:10648623, PMID:9663463). Conjugation of NEDD8 at Lys720 activates the ligase by enhancing ubiquitin chain formation, and a K720R mutant is catalytically crippled; ROC1 itself serves as the NEDD8-E3 promoting CUL1 neddylation, and nuclear import precedes and is required for this modification (PMID:10713156, PMID:10921923, PMID:11027288, PMID:12565873). SCF activity is gated by an assembly/disassembly cycle: CAND1 clamps unneddylated CUL1, occluding the Skp1- and NEDD8-binding sites to sequester it from substrate modules, while the COP9 signalosome removes NEDD8 through the JAMM metalloprotease of its CSN5/Jab1 subunit, with CAND1 and CSN acting on overlapping unneddylated CUL1 in a coordinated cycle (PMID:12504025, PMID:12504026, PMID:15537541, PMID:12183637, PMID:11337588, PMID:16036220). Through these SCF complexes CUL1 targets cyclin E, p27, cyclin D, p21, IκBα, β-catenin, and the F-box protein Skp2 itself for degradation, and loss of CUL1 causes cyclin E accumulation and failure of cell-cycle exit from worms to mice (PMID:8681378, PMID:10023660, PMID:9736735, PMID:10713156, PMID:10508527, PMID:10531039, PMID:11032804). CUL1 transcription is driven by c-Myc, coupling proliferative signaling to SCF(Skp2)-dependent p27 proteolysis (PMID:10970882).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1996 High

    Established CUL1 as a physiological negative regulator of the cell cycle, defining the founding cullin function before any biochemical mechanism was known.

    Evidence Genetic null analysis of cul-1/lin-19 in C. elegans showing tissue hyperplasia and failure of cell-cycle exit

    PMID:8681378

    Open questions at the time
    • Did not identify the biochemical activity of CUL-1
    • No substrate or partner identified at this stage
  2. 1998 High

    Identified CUL1 as an evolutionarily conserved SCF scaffold that physically assembles Skp1/Skp2/CDC34 into a functional ubiquitin ligase, connecting the genetic cell-cycle phenotype to a defined enzymatic complex.

    Evidence Yeast two-hybrid, in vitro binding, yeast cdc53 complementation, and Co-IP from synchronized human cells; CUL1 selectively binds SKP1 among cullins

    PMID:9430629 PMID:9636170 PMID:9663463 PMID:9736735

    Open questions at the time
    • Catalytic core (RING subunit) not yet defined
    • Substrate ubiquitination not reconstituted from purified components
  3. 1999 High

    Defined the RBX1/ROC1-CUL1 catalytic core and reconstituted phosphorylation-dependent substrate ubiquitination, showing CUL1 holds substrate receptor and catalytic module together to drive ubiquitin polymerization.

    Evidence In vitro reconstitution with purified Skp1, Cul1, HOS/β-TrCP, ROC1, ubiquitin, E1 and CDC34; Co-IP and dominant-negative β-TrCP in cells

    PMID:10023660 PMID:10230406

    Open questions at the time
    • Structural basis of scaffold rigidity not yet visualized
    • Regulation of assembly not addressed
  4. 1999 High

    Demonstrated that SCF(Cul1) is essential in mammalian development and required specifically for cyclin E proteolysis, linking the molecular machine to in vivo proliferation control.

    Evidence Cul1 knockout mice arresting at ~E6.5 with cyclin E protein (not mRNA) accumulation, immunohistochemistry and blastocyst outgrowth

    PMID:10508527 PMID:10531039

    Open questions at the time
    • Did not resolve which F-box receptor targets cyclin E in vivo
    • Cell-type-specific dependency mechanism unexplained
  5. 2000 High

    Revealed NEDD8 conjugation at CUL1 Lys720 as the activating switch that boosts ubiquitin chain formation and is required for nuclear localization and substrate ligation.

    Evidence In vitro NEDD8 conjugation and ubiquitin polymerization assays, K720R mutagenesis, subcellular fractionation and in vivo Co-IP with phospho-IκBα and β-catenin

    PMID:10713156 PMID:10921923 PMID:11027288

    Open questions at the time
    • Molecular mechanism by which NEDD8 enhances catalysis not structurally resolved
    • Identity of the NEDD8 E3 not yet established
  6. 2000 High

    Mapped the dual-domain architecture of CUL1 and connected Myc-driven CUL1 transcription to SCF(Skp2) substrate turnover, including autocatalytic Skp2 degradation.

    Evidence Deletion analysis and in vitro binding/ubiquitination; transcriptional reporter and rescue in c-myc-null MEFs; in vitro Skp2 ubiquitylation with recombinant Cul1-Roc1-Skp1

    PMID:10648623 PMID:10970882 PMID:11032804

    Open questions at the time
    • Quantitative contribution of Myc-CUL1 axis to proliferation in vivo unresolved
    • Regulation of autocatalytic vs. substrate ubiquitination not delineated
  7. 2001 High

    Identified the COP9 signalosome as the cellular NEDD8 deconjugase for CUL1, establishing a counter-regulatory arm to neddylation.

    Evidence Co-IP, in vitro deneddylation, and CSN loss-of-function in S. pombe causing accumulation of NEDD8-modified proteins; cyclin D1 ubiquitination by ROC1-CUL1 in vitro

    PMID:11311237 PMID:11337588

    Open questions at the time
    • Catalytic subunit of CSN not yet pinpointed
    • Physiological consequence of deneddylation not yet linked to cell cycle
  8. 2002 High

    Solved the SCF holoenzyme structure and identified CAND1 and CSN5/JAMM as the two regulators that control CUL1 assembly and deneddylation, building the dynamic SCF cycle model.

    Evidence X-ray structure of Cul1-Rbx1-Skp1-Skp2 with structure-guided mutagenesis; CSN5/Jab1 JAMM isopeptidase reconstitution and active-site mutagenesis; CAND1 Co-IP, in vitro ligase assay and siRNA

    PMID:11961546 PMID:12183637 PMID:12504025 PMID:12504026 PMID:12684064

    Open questions at the time
    • Structural basis of CAND1 exclusivity not yet resolved
    • Drosophila in vivo substrate spectrum not addressed by these in vitro/structural studies
  9. 2002 High

    Confirmed in vivo that NEDD8-modified CUL1 SCF is required for proteolysis of multiple substrates and that cullin choice partitions substrate processing within a pathway.

    Evidence Drosophila nedd8 and cul1 loss-of-function with substrate accumulation (Ci, Armadillo, Cyclin E) and epistasis analysis

    PMID:12231629

    Open questions at the time
    • Mechanism of cullin specificity (Cul1 vs Cul3) for Ci not resolved at molecular level
  10. 2003 Medium

    Distinguished DEN1 from CSN as a second NEDD8 protease with C-terminal hydrolase activity and defined ROC1 as the NEDD8-E3 for CUL1, refining the neddylation cycle enzymology.

    Evidence Purified DEN1 in vitro deconjugation assays; purified in vitro neddylation with ROC1 RING mutant H77A and in vivo stability assays

    PMID:12565873 PMID:12759363

    Open questions at the time
    • Relative physiological contributions of DEN1, CSN, and ROC1 not quantified
    • Single-lab biochemistry for ROC1 as NEDD8-E3
  11. 2004 High

    Provided the structural explanation for mutual exclusivity between CAND1 binding, Skp1 association, and neddylation, completing the mechanistic logic of SCF gating.

    Evidence X-ray structure of the Cand1-Cul1-Roc1 complex showing the HEAT-repeat superhelix clamping the Skp1 site and the NEDD8 lysine, with biochemical binding validation

    PMID:15537541

    Open questions at the time
    • Dynamics of CAND1-driven receptor exchange not captured by static structure
  12. 2005 High

    Linked CSN deneddylation to cell-cycle control and established that neddylation destabilizes cullins, with CSN recycling them into stable unneddylated forms.

    Evidence In vitro ubiquitination, anti-CSN2 microinjection, CSN2-CUL1 direct interaction and cell-cycle analysis; Drosophila CSN loss-of-function pulse-chase stability assays; CAND1/CSN mutual exclusivity by Co-IP/siRNA

    PMID:11967155 PMID:16036220 PMID:16127432

    Open questions at the time
    • Quantitative balance between neddylation-driven turnover and CSN recycling in vivo unresolved
  13. 2012 High

    Quantified the reciprocal inhibition between CSN and SCF and revealed GLMN as a RING-masking inhibitor, defining feedback that couples deneddylation to ligase occupancy state.

    Evidence Kinetic characterization of purified CSN on neddylated Cul1-Rbx1 with substrate/product inhibition; crystal structure of GLMN-RBX1-CUL1 with in vitro ubiquitin chain assay

    PMID:22748924 PMID:22767593

    Open questions at the time
    • Cellular conditions selecting CSN vs GLMN inhibition not defined
    • GLMN regulatory scope across CRLs not established
  14. 2022 Medium

    Extended CUL1's role to higher-order CRL architectures, showing it provides the catalytic neddylated module for receptor complexes that are themselves catalytically inert.

    Evidence Cryo-EM of CRL7FBXW8 plus in vitro neddylation/ubiquitination; Fbxw8-dependent Cul1-Cul7 heterodimer Co-IP from knockout mouse cells

    PMID:16880526 PMID:35982156

    Open questions at the time
    • Physiological substrates of the Cul1-Cul7 module beyond placental development not defined
  15. 2025 Medium

    Expanded the CUL1 regulatory and substrate landscape to context-specific outputs including autophagic substrate routing, viral oncoprotein control, and metabolic-enzyme turnover.

    Evidence Linkage-specific ubiquitin assays and autophagy reporters for K29-p27; Co-IP and ubiquitination of CUL1 by MARCHF8 in HPV+ cancer; phospho-OGT recognition by SCF(SKP2) under AMPK; CAND1 vs CAND2 exchange kinetics; cryo-EM of CRL1FBXO4/FBXO3

    PMID:38226814 PMID:39406020 PMID:39921442 PMID:40111576 PMID:41864201 PMID:42242895

    Open questions at the time
    • Most are single-lab findings without independent replication
    • Generality of K29-linked autophagic routing across substrates unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the SCF assembly/disassembly cycle is dynamically tuned in cells to select among the dozens of F-box receptors and to switch substrate fates (proteasomal vs autophagic) remains unresolved.
  • No integrated in-cell model coupling CAND1/CAND2 exchange, neddylation cycling, and receptor abundance
  • Determinants of ubiquitin linkage choice by SCF(CUL1) not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016874 ligase activity 3 GO:0060090 molecular adaptor activity 3 GO:0005198 structural molecule activity 2
Localization
GO:0005634 nucleus 2 GO:0005654 nucleoplasm 2
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3
Partners
BTRCCAND1CDC34CUL7GLMNRBX1SKP1SKP2
Complex memberships
CAND1-CUL1-ROC1 complexCUL1-CUL7 heterodimerCUL1-RBX1/ROC1 catalytic coreSCF (Skp1-CUL1-F-box) E3 ubiquitin ligase

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Crystal structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF complex reveals that Cul1 is an elongated protein with a long stalk (three repeats of a novel five-helix motif) that binds Skp1-F boxSkp2 at its tip, and a globular domain that binds Rbx1 through an intermolecular beta-sheet to form a two-subunit catalytic core that recruits the ubiquitin-conjugating enzyme. Cul1 acts as a rigid scaffold holding Skp1-FboxSkp2 and Rbx1 over 100 Å apart; mutations designed to eliminate scaffold rigidity impair function. X-ray crystallography with functional validation by structure-guided mutagenesis Nature High 11961546
2002 The Jab1/Csn5 subunit of the COP9 signalosome (CSN) cleaves Nedd8 from Cul1 via its JAMM (Jab1/MPN domain metalloenzyme) motif; metal chelators and point mutations within JAMM abolish CSN-dependent Nedd8 deconjugation from Cul1 without disrupting CSN complex assembly. In vitro Nedd8 isopeptidase assay, active-site mutagenesis, metal chelation Science High 12183637
2001 The COP9 signalosome (CSN) associates with multiple cullins and promotes cleavage of the ubiquitin-like protein NEDD8 from S. pombe CUL1 both in vivo and in vitro; CSN-deficient cells accumulate multiple NEDD8-modified proteins. Co-immunoprecipitation, in vitro deneddylation assay, genetic loss-of-function in S. pombe Science High 11337588
1996 C. elegans cul-1 (formerly lin-19) is required for cell-cycle exit; null mutations cause hyperplasia of all tissues, accelerated G1-to-S progression, and failure to transition from the cell cycle to G0 or apoptosis, establishing CUL-1 as a negative regulator of the cell cycle and founding member of the cullin family. Genetic loss-of-function (null mutations), phenotypic analysis in C. elegans Cell High 8681378
1999 Human beta-TrCP forms a novel SCF complex with Skp1 and Cul1; this complex interacts with beta-catenin in vivo, and dominant-negative beta-TrCP specifically stabilizes beta-catenin, demonstrating that SCF(beta-TrCP/Cul1) is a ubiquitin ligase mediating beta-catenin degradation. Co-immunoprecipitation, dominant-negative overexpression in cells Oncogene Medium 10023660
1998 Human CUL-1 associates with SKP1 and SKP2 in vivo and, via antisense inhibition of CUL-1, SKP1, or SKP2, p21(CIP1/WAF1) and cyclin D proteins selectively accumulate, indicating the SKP1/SKP2/CUL-1 complex functions as an E3 ligase targeting cyclin D and p21 for ubiquitin-dependent degradation. Co-immunoprecipitation, antisense oligonucleotide knockdown with Western blot readout Proceedings of the National Academy of Sciences of the United States of America Medium 9736735
2000 Nedd8 modification of Cul-1 at Lys720 is required for optimal SCF(beta-TrCP)-dependent ubiquitination of IkappaBalpha; Nedd8-conjugated Cul-1 associates with phospho-IkappaBalpha and beta-catenin in vivo; K720R mutant Cul-1 only weakly supports IkappaBalpha ubiquitination. In vitro ubiquitination assay, site-directed mutagenesis (K720R), co-immunoprecipitation Molecular and cellular biology High 10713156
1999 ROC1 heterodimerizes with Cul1 to form the catalytic core of the SCFHOS-ROC1 holenzyme; in vitro reconstitution with purified Skp1, Cul1, HOS/beta-TRCP, and ROC1 reconstitutes phosphorylation-dependent IkappaBalpha ubiquitination in the presence of ubiquitin, E1, and Cdc34. ROC1 uniquely supports ubiquitin polymerization by heterodimerizing with Cul1. In vitro ubiquitination reconstitution with purified components, Co-IP Molecular cell High 10230406
2002 p120(CAND1) selectively binds unneddylated CUL1, forms a ternary complex with CUL1 and ROC1, dissociates SKP1 from CUL1, and inhibits SCF ligase activity in vitro. CUL1 neddylation causes CAND1 dissociation. Suppression of CAND1 increases the CUL1-SKP1 complex level in vivo. Co-immunoprecipitation, in vitro ubiquitination assay, siRNA knockdown Molecular cell High 12504025 12504026
2004 Crystal structure of the Cand1-Cul1-Roc1 complex shows Cand1 adopts a sinuous HEAT-repeat superhelix that clamps around Cul1: one end occludes the Skp1 adaptor-binding site on Cul1 and the other buries the Cul1 lysine modified by Nedd8, explaining mutual exclusivity between Cand1 binding and neddylation/Skp1 association. X-ray crystallography plus biochemical binding assays Cell High 15537541
2000 Conjugation of Nedd8 to CUL1 at Lys720 by HeLa extracts or purified Nedd8 conjugation system (APP-BP1/Uba3, Ubc12, Nedd8) markedly enhances the ability of the ROC1-CUL1 complex to promote ubiquitin polymerization. K720R mutation eliminates Nedd8 modification and abolishes E3 ligase activation. In vitro Nedd8 conjugation with purified components, ubiquitin polymerization assay, site-directed mutagenesis The Journal of biological chemistry High 10921923
2000 The N-terminus of CUL1 is necessary and sufficient for binding Skp1 but lacks ROC1-binding activity and is inactive in catalyzing ubiquitin ligation. The C-terminus of CUL1 interacts with ROC1 through the cullin consensus domain to form a core ubiquitin ligase, establishing CUL1 as a dual-function molecule. Deletion analysis, in vitro binding assays, in vitro ubiquitination assay, dominant-negative cell experiments Molecular and cellular biology High 10648623
1998 Human CUL-1 directly interacts with hSKP1 (identified by two-hybrid) and SKP2 in vitro, forming an SCF-like particle. hCUL1 complements yeast cdc53(ts) growth defects and assembles functional chimeric ubiquitin ligase complexes with yeast SCF components, demonstrating evolutionary conservation of the SCF ubiquitin ligase function. Yeast two-hybrid, in vitro binding assay, yeast complementation, ubiquitin ligase activity assay Proceedings of the National Academy of Sciences of the United States of America High 9636170
1998 Human CUL1, but not CUL2, 3, 4A, or 5, selectively interacts with SKP1 via their N-terminal domains; this CUL1-SKP1 interaction is required for CUL1 to associate with SKP2. Co-immunoprecipitation, in vitro binding with N-terminal domain mutants Cell growth & differentiation Medium 9663463
1998 Human CUL-1 associates with SKP1, SKP2, CDC34, and cyclin A in vivo, forming an SCF-type complex; the p45(SKP2)-CUL-1-p19(SKP1) complex assembly is governed in part by periodic S-phase accumulation of SKP2 and by the SKP2-bound cyclin A-CDK2. Co-immunoprecipitation in synchronized cells The EMBO journal Medium 9430629
1999 Cul1 knockout mice die around embryonic day 6.5 before gastrulation; Cul1-null embryos and blastocyst outgrowths exhibit highly elevated cyclin E protein (but not mRNA), establishing that SCF(Cul1) activity is required for cyclin E proteolysis during early mammalian development. Gene knockout in mice, Western blot for cyclin E protein vs. mRNA Nature genetics High 10508527 10531039
1999 Cul1 deletion mice arrest at ~E6.5 with cyclin E protein accumulation in all cells; trophoblast giant cells continue to endocycle despite elevated cyclin E, demonstrating cell-type-specific dependency on SCF(Cul1) for cyclin E degradation. Gene knockout in mice, immunohistochemistry, blastocyst outgrowth cultures Current biology High 10531039
2000 c-Myc directly activates Cul1 gene transcription; enforced Cul1 expression alone rescues the slow-growth phenotype of c-myc-null MEFs and restores p27(kip1) ubiquitination and degradation in lysates from c-myc-/- MEFs or density-arrested human fibroblasts, linking Myc-driven transcription to SCF(Skp2)-dependent p27 proteolysis. Transcriptional reporter assay, reconstitution in cell lysates, antisense p27 rescue, cell growth assay in MEFs Genes & development High 10970882
2000 The F-box protein Skp2 is ubiquitylated by a Cul1-Roc1-Skp1 core complex in vitro; Cul1 interference in serum-deprived cells induces Skp2 expression, and Skp2 sequences required for Cul1 binding are necessary for its rapid degradation in G0/G1, suggesting autocatalytic SCF-mediated Skp2 degradation. In vitro ubiquitylation assay with recombinant Cul1-Roc1-Skp1, dominant-negative Cul1, domain mapping The EMBO journal High 11032804
2000 The C-terminal sequence of CUL1 and ROC1 binding are dually required for nuclear localization and NEDD8 modification of CUL1 in vivo; ROC1 promotes CUL1 nuclear accumulation to facilitate NEDD8 modification; nuclear import precedes and is required for NEDD8 modification; disrupting NEDD8 modification diminishes IkappaBalpha ubiquitin ligase activity. Subcellular fractionation, immunofluorescence, site-directed mutagenesis, in vivo/in vitro NEDD8 conjugation assay, ubiquitin ligase activity assay Molecular and cellular biology High 11027288
2002 In Drosophila, Nedd8 modifies Cul1 and Cul1 mutants accumulate Cubitus interruptus (Ci), Armadillo (Arm), and Cyclin E, demonstrating that Cul1-based SCF complexes require Nedd8 modification for proteolytic processing of these substrates. Anterior to the morphogenetic furrow, Ci proteolytic processing (PKA-dependent) requires Nedd8-modified SCF(Slimb); posterior Ci degradation is Cul3-dependent and PKA-independent. Genetic loss-of-function in Drosophila (nedd8 and cul1 mutants), immunostaining for substrate accumulation, epistasis analysis Genes & development High 12231629
2003 DEN1 is a Nedd8-specific protease that selectively deconjugates Nedd8 from CUL1: at low concentrations it processes hyper-neddylated CUL1 to a mononeddylated form; at higher concentrations it removes Nedd8 completely. DEN1 also processes Nedd8 C-terminal derivatives, distinguishing it from CSN which cleaves the Lys720-Nedd8 isopeptide efficiently but lacks C-terminal hydrolase activity. Purified recombinant DEN1, in vitro deconjugation assay, biochemical characterization The Journal of biological chemistry High 12759363
2002 p120(CAND1) (TIP120A) physically associates with CUL1 in the nucleus via a central region of CUL1 distinct from the Skp1 and Rbx1 binding sites, and specifically interacts with unneddylated CUL1; the CUL1-CAND1 complex does not include Skp1. Tandem affinity purification, immunoprecipitation, immunofluorescence, co-immunoprecipitation with neddylation-site mutants Biochemical and biophysical research communications Medium 12684064
2003 Roc1 functions as a Nedd8-E3 ligase toward CUL1: Roc1 binds Ubc12 (E2 for Nedd8) via its RING finger; RING finger mutant H77A abolishes Ubc12 binding; in a purified in vitro neddylation system using bacterially expressed CUL1/Roc1, Roc1 promotes CUL1 neddylation. Neddylation of CUL1 also promotes ubiquitination and degradation of the CUL1/Roc1 complex; K720R non-neddylatable CUL1 is more stable than wild-type. In vitro neddylation assay with purified components, RING finger mutagenesis, in vivo stability assay Biochemical and biophysical research communications Medium 12565873
2005 CSN deneddylation of CUL1 promotes p27(kip1) stabilization and inhibits G1-S progression; CSN2's N-terminal half directly interacts with CUL1; anti-CSN2 antibodies cause neddylated CUL1 accumulation in HeLa extracts; microinjected CSN complex blocks G1/S transition; these effects require deneddylation activity. In vitro ubiquitination assay, antibody microinjection, CSN2-CUL1 direct interaction assay, cell-cycle analysis Current biology High 11967155
2005 Neddylation renders Cul1 and Cul3 unstable; in CSN-deficient cells (lacking isopeptidase activity) Cul1 and Cul3 proteins are unstable. The unneddylatable form of Cul1 is stable, and Nedd8 itself is degraded en bloc with neddylated cullins. CSN deneddylation recycles unstable neddylated cullins into stable unneddylated forms. CSN loss-of-function in Drosophila, pulse-chase stability assays, unneddylatable mutant analysis Nature cell biology High 16127432
2012 CSN is an efficient Nedd8 deconjugase (kcat ~1 s−1, Km ~200 nM for neddylated Cul1-Rbx1). Assembly with Skp1-F-box complexes markedly inhibits deneddylation; substrate further inhibits deneddylation; product (deneddylated Cul1) inhibits CSN by tight binding; reciprocally, CSN inhibits ubiquitin ligase activity of deneddylated Cul1. Kinetic characterization of purified CSN in vitro, reconstituted SCF complexes, substrate addition experiments The Journal of biological chemistry High 22767593
2012 Crystal structure of Glomulin (GLMN)-RBX1-CUL1 fragment complex shows GLMN adopts a HEAT-like repeat fold that tightly binds the E2-interacting surface of RBX1, thereby inhibiting CRL-mediated ubiquitin chain formation by the E2 CDC34. This reveals a mechanism of RING E3 inhibition by masking the E2-binding surface. X-ray crystallography plus biochemical ubiquitin chain assay, disease-mutation analysis Molecular cell High 22748924
2001 ROC1-CUL1 (but not ROC1-CUL2 or ROC1-CUL4) immunocomplexes promote polyubiquitination of bacterially purified cyclin D1 in vitro; RING finger mutations in ROC1 eliminate ubiquitin ligase activity toward cyclin D1; ROC1 also binds all three D-type cyclins in vivo. In vitro ubiquitination assay, co-immunoprecipitation, RING finger mutagenesis FEBS letters Medium 11311237
2005 CAND1 and CSN bind unneddylated CUL1 in a mutually exclusive fashion; CAND1 inhibits CSN binding to CUL1 (which requires the four-helix bundle in CUL1's C-terminal domain); yet CAND1 greatly facilitates CSN-mediated deneddylation of CUL1 in vitro in a CUL1-binding-dependent manner. Co-immunoprecipitation, siRNA knockdown, in vitro deneddylation assay Biochemical and biophysical research communications Medium 16036220
2006 Fbxw8 is required for Cul7 to form a heterodimeric complex with Cul1; in Fbxw8-/- mouse cells Cul7 does not associate with Cul1. This Cul1-Cul7 partnership is essential for placental development. Fbxw8 knockout mouse, co-immunoprecipitation from mouse cells Molecular and cellular biology Medium 16880526
2022 Cryo-EM structure of CRL7FBXW8 reveals CUL7 binds FBXW8 in an F-box-independent mode and the RBX1 RING domain is constrained in an orientation incompatible with E2~NEDD8 or E2~ubiquitin binding. CRL7 itself lacks auto-neddylation and ubiquitination activities and instead acts as a substrate receptor linked to a neddylated CUL1-RBX1 catalytic module for ubiquitination. Cryo-EM structure determination, in vitro neddylation and ubiquitination assays with purified components Nature structural & molecular biology High 35982156
2006 Cul1 is ubiquitylated in vivo; ubiquitylation of Cul1 promotes its binding to the S5a subunit of the 19S proteasome sub-complex without affecting Cul1 stability, demonstrating physical coupling of the SCF ubiquitin ligase to the proteasome. Co-immunoprecipitation, in vivo ubiquitylation assay, proteasome binding assay Cell division Medium 16759355
2015 In yeast, the cullin Cdc53/Cul1 promotes ubiquitylation and degradation of the F-box protein Met30 that is dissociated from Skp1, in a Skp1-independent but Cdc53/Rbx1/Cdc34-dependent manner, revealing a non-canonical CUL1 ubiquitin ligase sub-complex for F-box protein homeostasis. Yeast genetic analysis, in vivo ubiquitylation assay, Co-IP PLoS genetics Medium 26656496
2024 Cryo-EM structure of CRL1FBXO4 shows FBXO4 interacts with both SKP1 and CUL1 via hydrophobic and electrostatic interactions; two FBXO4 subunits form a domain-swapped dimer creating a symmetric CRL1FBXO4 homodimer architecture. Cryo-EM structure determination Biochemical and biophysical research communications Medium 39406020
2025 Cryo-EM structure of SCF(FBXO3) at 3.70 Å shows FBXO3's F-box domain associates with SKP1 via hydrophobic interactions and contacts CUL1's N-terminal region via hydrophobic interactions; the RBX1 globular region is close to FBXO3's ApaG domain in a closed conformation, suggesting CUL1 neddylation is required for high E3 activity. Cryo-EM structure determination Proteins Medium 39921442
2024 MARCHF8 binds to and ubiquitinates CUL1 (and UBE2L3), leading to their proteasomal degradation in HPV-positive head and neck cancer cells. This degradation stabilizes HPV16 E7 by blocking SCF(CUL1)-mediated E7 ubiquitination. Conversely, overexpression of CUL1 decreases E7 levels and suppresses tumor growth in vivo. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown/overexpression with Western blot, in vivo xenograft Journal of virology Medium 38226814
2025 NEDD8-mediated CUL1 neddylation enhances SCF(SKP2) E3 ligase activity to add K29-linked polyubiquitin chains to p27, promoting autophagic (NBR1-mediated) rather than proteasomal degradation of p27 in sorafenib-resistant liver cancer cells. Ubiquitin linkage-specific assay (K27/29/33/48/63 ubiquitin mutants), CUL1 knockdown, mCherry-eGFP-LC3B autophagy reporter Cell biology and toxicology Medium 40111576
2026 In serum-deprived 3T3-L1 cells, AMPK activation induces phosphorylation of OGT at Thr444, which triggers OGT proteolysis by the CUL1/SKP1/SKP2 E3 ubiquitin ligase. SKP2 knockdown blocks this degradation, establishing phospho-dependent OGT recognition by the SCF(SKP2) complex. siRNA knockdown, co-immunoprecipitation, AMPK inhibitor/activator treatment, phospho-site identification Biomolecules & therapeutics Medium 42242895
2024 CAND1 displays reduced efficiency compared to its paralog CAND2 in CRL1 disassembly (substrate receptor exchange), while both proteins promote CRL4-mediated protein degradation with comparable kinetic parameters. Real-time kinetic analyses reveal distinct biochemical efficiencies of CAND1 vs CAND2 specifically for CUL1-based SCF complexes. Real-time kinetic analyses, quantitative interaction proteomics, genetic perturbation Structure Medium 41864201

Source papers

Stage 0 corpus · 77 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Structure of the Cul1-Rbx1-Skp1-F boxSkp2 SCF ubiquitin ligase complex. Nature 1246 11961546
2002 Role of predicted metalloprotease motif of Jab1/Csn5 in cleavage of Nedd8 from Cul1. Science (New York, N.Y.) 604 12183637
2001 Promotion of NEDD-CUL1 conjugate cleavage by COP9 signalosome. Science (New York, N.Y.) 584 11337588
1996 cul-1 is required for cell cycle exit in C. elegans and identifies a novel gene family. Cell 397 8681378
1999 The human F box protein beta-Trcp associates with the Cul1/Skp1 complex and regulates the stability of beta-catenin. Oncogene 396 10023660
1998 Human CUL-1 associates with the SKP1/SKP2 complex and regulates p21(CIP1/WAF1) and cyclin D proteins. Proceedings of the National Academy of Sciences of the United States of America 377 9736735
2000 Nedd8 modification of cul-1 activates SCF(beta(TrCP))-dependent ubiquitination of IkappaBalpha. Molecular and cellular biology 327 10713156
1999 Recruitment of a ROC1-CUL1 ubiquitin ligase by Skp1 and HOS to catalyze the ubiquitination of I kappa B alpha. Molecular cell 304 10230406
2002 NEDD8 modification of CUL1 dissociates p120(CAND1), an inhibitor of CUL1-SKP1 binding and SCF ligases. Molecular cell 270 12504025
2002 CAND1 binds to unneddylated CUL1 and regulates the formation of SCF ubiquitin E3 ligase complex. Molecular cell 261 12504026
2014 Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma. Cancer research 259 25488749
2004 Structure of the Cand1-Cul1-Roc1 complex reveals regulatory mechanisms for the assembly of the multisubunit cullin-dependent ubiquitin ligases. Cell 240 15537541
1998 Association of human CUL-1 and ubiquitin-conjugating enzyme CDC34 with the F-box protein p45(SKP2): evidence for evolutionary conservation in the subunit composition of the CDC34-SCF pathway. The EMBO journal 178 9430629
2000 Conjugation of Nedd8 to CUL1 enhances the ability of the ROC1-CUL1 complex to promote ubiquitin polymerization. The Journal of biological chemistry 170 10921923
2000 Myc-enhanced expression of Cul1 promotes ubiquitin-dependent proteolysis and cell cycle progression. Genes & development 169 10970882
2002 Distinct protein degradation mechanisms mediated by Cul1 and Cul3 controlling Ci stability in Drosophila eye development. Genes & development 163 12231629
2003 DEN1 is a dual function protease capable of processing the C terminus of Nedd8 and deconjugating hyper-neddylated CUL1. The Journal of biological chemistry 157 12759363
2000 The F-box protein Skp2 is a ubiquitylation target of a Cul1-based core ubiquitin ligase complex: evidence for a role of Cul1 in the suppression of Skp2 expression in quiescent fibroblasts. The EMBO journal 156 11032804
1999 Loss of Cul1 results in early embryonic lethality and dysregulation of cyclin E. Nature genetics 152 10508527
2005 Neddylation and deneddylation regulate Cul1 and Cul3 protein accumulation. Nature cell biology 150 16127432
2002 The COP9 signalosome inhibits p27(kip1) degradation and impedes G1-S phase progression via deneddylation of SCF Cul1. Current biology : CB 135 11967155
1999 Deletion of the Cul1 gene in mice causes arrest in early embryogenesis and accumulation of cyclin E. Current biology : CB 128 10531039
1998 Human CUL1 forms an evolutionarily conserved ubiquitin ligase complex (SCF) with SKP1 and an F-box protein. Proceedings of the National Academy of Sciences of the United States of America 119 9636170
1998 Human CUL-1, but not other cullin family members, selectively interacts with SKP1 to form a complex with SKP2 and cyclin A. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 118 9663463
2000 The CUL1 C-terminal sequence and ROC1 are required for efficient nuclear accumulation, NEDD8 modification, and ubiquitin ligase activity of CUL1. Molecular and cellular biology 117 11027288
2011 Two ubiquitin ligases, APC/C-Cdh1 and SKP1-CUL1-F (SCF)-beta-TrCP, sequentially regulate glycolysis during the cell cycle. Proceedings of the National Academy of Sciences of the United States of America 116 21402913
2012 Deconjugation of Nedd8 from Cul1 is directly regulated by Skp1-F-box and substrate, and the COP9 signalosome inhibits deneddylated SCF by a noncatalytic mechanism. The Journal of biological chemistry 109 22767593
2000 The SCF(HOS/beta-TRCP)-ROC1 E3 ubiquitin ligase utilizes two distinct domains within CUL1 for substrate targeting and ubiquitin ligation. Molecular and cellular biology 99 10648623
2003 Nedd8-modification of Cul1 is promoted by Roc1 as a Nedd8-E3 ligase and regulates its stability. Biochemical and biophysical research communications 82 12565873
2013 Genetically engineered mouse models for functional studies of SKP1-CUL1-F-box-protein (SCF) E3 ubiquitin ligases. Cell research 79 23528706
2005 Characterization of a novel temperature-sensitive allele of the CUL1/AXR6 subunit of SCF ubiquitin-ligases. The Plant journal : for cell and molecular biology 71 16045473
2012 Structure of a glomulin-RBX1-CUL1 complex: inhibition of a RING E3 ligase through masking of its E2-binding surface. Molecular cell 70 22748924
2016 Protein Kinase R Degradation Is Essential for Rift Valley Fever Virus Infection and Is Regulated by SKP1-CUL1-F-box (SCF)FBXW11-NSs E3 Ligase. PLoS pathogens 62 26837067
2011 The SKP1-Cul1-F-box and leucine-rich repeat protein 4 (SCF-FbxL4) ubiquitin ligase regulates lysine demethylase 4A (KDM4A)/Jumonji domain-containing 2A (JMJD2A) protein. The Journal of biological chemistry 56 21757720
2003 Preferential interaction of TIP120A with Cul1 that is not modified by NEDD8 and not associated with Skp1. Biochemical and biophysical research communications 53 12684064
2007 Thiazolidinediones modulate the expression of beta-catenin and other cell-cycle regulatory proteins by targeting the F-box proteins of Skp1-Cul1-F-box protein E3 ubiquitin ligase independently of peroxisome proliferator-activated receptor gamma. Molecular pharmacology 49 17569795
2006 Fbxw8 is essential for Cul1-Cul7 complex formation and for placental development. Molecular and cellular biology 47 16880526
2013 Role of SKP1-CUL1-F-box-protein (SCF) E3 ubiquitin ligases in skin cancer. Journal of genetics and genomics = Yi chuan xue bao 42 23522382
2012 Skp1-Cul1-F-box ubiquitin ligase (SCF(βTrCP))-mediated destruction of the ubiquitin-specific protease USP37 during G2-phase promotes mitotic entry. The Journal of biological chemistry 42 23027877
2011 Drosophila homeodomain-interacting protein kinase inhibits the Skp1-Cul1-F-box E3 ligase complex to dually promote Wingless and Hedgehog signaling. Proceedings of the National Academy of Sciences of the United States of America 39 21628596
2010 Increased Cul1 expression promotes melanoma cell proliferation through regulating p27 expression. International journal of oncology 37 20878082
2005 CAND1 enhances deneddylation of CUL1 by COP9 signalosome. Biochemical and biophysical research communications 34 16036220
2018 CUL1 promotes breast cancer metastasis through regulating EZH2-induced the autocrine expression of the cytokines CXCL8 and IL11. Cell death & disease 33 30578411
2020 Gossypol inhibits cullin neddylation by targeting SAG-CUL5 and RBX1-CUL1 complexes. Neoplasia (New York, N.Y.) 30 32145688
2013 CUL1 promotes trophoblast cell invasion at the maternal-fetal interface. Cell death & disease 30 23429288
2018 A Structure-Based Strategy for Engineering Selective Ubiquitin Variant Inhibitors of Skp1-Cul1-F-Box Ubiquitin Ligases. Structure (London, England : 1993) 28 30033217
2013 Substrate binding promotes formation of the Skp1-Cul1-Fbxl3 (SCF(Fbxl3)) protein complex. The Journal of biological chemistry 28 24085301
2021 Reduced SKP1 and CUL1 expression underlies increases in Cyclin E1 and chromosome instability in cellular precursors of high-grade serous ovarian cancer. British journal of cancer 27 33731859
2005 CUL1, a component of E3 ubiquitin ligase, alters lymphocyte signal transduction with possible effect on rheumatoid arthritis. Genes and immunity 26 15759013
2022 Structure of CRL7FBXW8 reveals coupling with CUL1-RBX1/ROC1 for multi-cullin-RING E3-catalyzed ubiquitin ligation. Nature structural & molecular biology 24 35982156
2008 UV-induced degradation of securin is mediated by SKP1-CUL1-beta TrCP E3 ubiquitin ligase. Journal of cell science 24 18460583
2001 In vitro ubiquitination of cyclin D1 by ROC1-CUL1 and ROC1-CUL3. FEBS letters 24 11311237
2021 microRNA-377-3p inhibits osteosarcoma progression by targeting CUL1 and regulating Wnt/β-catenin signaling pathway. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 14 34133001
2025 SKP1-CUL1-F-box: Key molecular targets affecting disease progression. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 12 39812503
2024 The membrane-associated ubiquitin ligase MARCHF8 stabilizes the human papillomavirus oncoprotein E7 by degrading CUL1 and UBE2L3 in head and neck cancer. Journal of virology 11 38226814
2008 The proto-oncogene Int6 is essential for neddylation of Cul1 and Cul3 in Drosophila. PloS one 11 18493598
2020 CUL1-Mediated Organelle Fission Pathway Inhibits the Development of Chronic Obstructive Pulmonary Disease. Computational and mathematical methods in medicine 9 32565880
2015 Cul1 promotes melanoma cell proliferation by promoting DEPTOR degradation and enhancing cap-dependent translation. Oncology reports 9 26717892
2000 Temporal and spatial expression of the cell-cycle regulator cul-1 in Drosophila and its stimulation by radiation-induced apoptosis. The Journal of experimental biology 9 10952875
2025 CUL1-neddylation contributes to K29-linked ubiquitination on p27 for autophagic degradation in sorafenib-resistant liver cancer. Cell biology and toxicology 8 40111576
2015 Skp1 Independent Function of Cdc53/Cul1 in F-box Protein Homeostasis. PLoS genetics 8 26656496
2006 Modification of Cul1 regulates its association with proteasomal subunits. Cell division 8 16759355
2020 Plant systemic acquired resistance compound salicylic acid as a potent inhibitor against SCF (SKP1-CUL1-F-box protein) mediated complex in Fusarium oxysporum by homology modeling and molecular dynamics simulations. Journal of biomolecular structure & dynamics 7 33047664
2021 New insights into the roles of CUL1 in mouse placenta development. Biochemical and biophysical research communications 6 33933992
2019 CUL1 Knockdown Attenuates the Adhesion, Invasion, and Migration of Triple-Negative Breast Cancer Cells via Inhibition of Epithelial-Mesenchymal Transition. Pathology oncology research : POR 6 31175550
2017 Characterization and comparative expression analysis of CUL1 genes in rice. Genes & genomics 6 29892794
2024 Structure of the CUL1-RBX1-SKP1-FBXO4 SCF ubiquitin ligase complex. Biochemical and biophysical research communications 5 39406020
2025 5'tiRNA-35-GlyTCC-3 and 5'tiRNA-33-CysGCA-11 target BMP6, CUL1 and SPR of non-syndromic cleft palate. BMC oral health 4 40012056
2024 CUL1 exacerbates glucocorticoid-induced osteoporosis by enhancing ASAP1 ubiquitination. Hormones (Athens, Greece) 3 39287759
2016 Expression of CUL1 correlates with tumour-grade and recurrence in urothelial carcinoma. ANZ journal of surgery 3 27312089
2025 Structural Insight Into the SKP1-CUL1-FBXO3-RBX1 Complex. Proteins 2 39921442
2023 RNF126, 168 and CUL1: The Potential Utilization of Multi-Functional E3 Ubiquitin Ligases in Genome Maintenance for Cancer Therapy. Biomedicines 2 37760968
2022 Inhibitory effect of CUL1 on atherosclerosis through the p53 pathway. Annals of translational medicine 2 36267727
2025 CUL1 variants cause severe neurodevelopmental disorders: Insights from human genetics and a zebrafish model of microcephaly. HGG advances 1 41189326
2026 CAND1 and CAND2 drive CUL4 substrate receptor exchange with largely comparable biochemical efficiency, unlike their relative effects on CUL1. Structure (London, England : 1993) 0 41864201
2026 Serum Starvation Promotes the Proteolysis of OGT by Activating AMPK and the CUL1/SKP1/SKP2 E3 Ubiquitin Ligase in 3T3-L1 Cells. Biomolecules & therapeutics 0 42242895
2023 The membrane-associated ubiquitin ligase MARCHF8 stabilizes the human papillomavirus oncoprotein E7 by degrading CUL1 and UBE2L3 in head and neck cancer. bioRxiv : the preprint server for biology 0 37961092

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