Cdc4 is the WD40-repeat F-box protein that serves as the substrate-recognition subunit of the SCF(Cdc4) ubiquitin ligase (Skp1-Cdc53/cullin-Hrt1/Rbx1-Cdc4) of Saccharomyces cerevisiae and is the founding member of the FBXW7 family. Its N-terminal region carries a nuclear localisation signal and a dimerisation (D) domain, the F-box binds Skp1 to tether it to the Cdc53 scaffold, and its C-terminal eight-bladed WD40 beta-propeller reads short phosphorylated degrons (Cdc4 phosphodegrons), typically diphosphorylated or clustered suboptimal motifs generated by Cdc28/Cdk1, Pho85, Mck1 or Cdc7 priming. Cdc4 has no catalytic activity: it captures phosphorylated substrates and positions them for polyubiquitination by the Cdc34 E2 bound to the Cdc53-Hrt1 core, which commits them to proteasomal degradation. Its defining substrate is the Clb-Cdk inhibitor Sic1, whose multisite-phosphorylation-gated destruction at Start releases Clb5/6-Cdc28 to initiate DNA replication; cdc4 mutants therefore arrest at G1/S with replicated-DNA-negative, multibudded cells, and additionally show a Sic1-independent block at G2/M. Other substrates include the pheromone-arrest CKI Far1 (degraded only in the nucleus, where Cdc4 resides), the replication factor Cdc6, the transcription factors Gcn4, Swi5, Tec1 and Ash1, the calcineurin inhibitor Rcn1, the cohesin acetyltransferase Eco1, the deacetylase Hst3, kinetochore subunits, and the MAPKK Ste7, whose SCF(Cdc4)-dependent ubiquitination tunes MAPK specificity. The WD40 propeller also binds ubiquitin at a surface distinct from the degron pocket, which promotes Cdc4 autoubiquitination and turnover. Cdc4 is exclusively nuclear and is essential for mitotic growth and for several steps of meiosis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000082 G1/S transition of mitotic cell cycle | IMP PMID:10409741 Cdc4, a protein required for the onset of S phase, serves an... | ACCEPT | Summary: Cdc4 drives the G1/S transition as the WD40 F-box substrate receptor of SCF(Cdc4): it captures multisite-phosphorylated Sic1 for Cdc34-dependent ubiquitination and proteasomal destruction, releasing Clb5/6-Cdc28 to initiate DNA replication. Reason: Core biological process. Sic1 destruction at Start is the founding SCF paradigm: cdc4 mutants arrest at G1/S with stabilised Sic1, the arrest is bypassed by SIC1 deletion, and Cdc4-Skp1 is the receptor that binds phospho-Sic1 in the reconstituted SCF(Cdc4) ubiquitination reaction. Cdc4 performs the recognition step itself (the participation test is met), and the same term is carried by the human CKI adaptor SKP2 and used for Cdc4 in the repository G1/S module. This paper re-examined cdc4 alleles and confirmed that the G1/S block of cdc4-12 and cdc4-delta cells is abolished by SIC1 deletion. Supporting Evidence: PMID:10409741 Sic1, necessary for G(1)/S transition PMID:10409741 abolished by the deletion of the SIC1 gene file:yeast/CDC4/CDC4-deep-research-falcon.md Sic1 destruction releases S-phase Clb–Cdk activity, promoting the G1/S transition and DNA-replication initiation. |
| GO:0000082 G1/S transition of mitotic cell cycle | NAS PMID:14747994 Functional interaction of 13 yeast SCF complexes with a set ... | ACCEPT | Summary: Cdc4 drives the G1/S transition as the WD40 F-box substrate receptor of SCF(Cdc4): it captures multisite-phosphorylated Sic1 for Cdc34-dependent ubiquitination and proteasomal destruction, releasing Clb5/6-Cdc28 to initiate DNA replication. Reason: Core biological process. Sic1 destruction at Start is the founding SCF paradigm: cdc4 mutants arrest at G1/S with stabilised Sic1, the arrest is bypassed by SIC1 deletion, and Cdc4-Skp1 is the receptor that binds phospho-Sic1 in the reconstituted SCF(Cdc4) ubiquitination reaction. Cdc4 performs the recognition step itself (the participation test is met), and the same term is carried by the human CKI adaptor SKP2 and used for Cdc4 in the repository G1/S module. The author statement accompanies a reconstitution in which purified SCF(Cdc4) ubiquitinates Sic1 with Cdc34 (and Ubc4), the biochemical basis of the transition. Supporting Evidence: PMID:14747994 ubiquitination of Sic1 by the reconstituted SCF(Cdc4) complex was specifically PMID:14747994 catalyzed by two of the five E2 enzymes tested in vitro; Cdc34 and Ubc4 PMID:7954792 Proteolysis of a cyclin-specific inhibitor of Cdc28 is therefore an essential aspect of the G1 to S phase transition. |
| GO:0000086 G2/M transition of mitotic cell cycle | IGI PMID:7954792 The B-type cyclin kinase inhibitor p40SIC1 controls the G1 t... | KEEP AS NON CORE | Summary: Cdc4 has a second, mechanistically less-defined role at the G2/M transition: cdc4 mutants relieved of their Sic1-dependent G1 block by SIC1 deletion arrest before anaphase, and that preanaphase arrest is relieved by deleting PDS1. Reason: The G2/M requirement is genuine (cdc4-delta sic1-delta and cdc4-12 sic1-delta cells arrest at G2/M, and cdc4 alleles suppress cdc20-1), but the substrate through which SCF(Cdc4) acts here has not been identified, and it is a second role rather than the defining function of the adaptor. Kept as non-core, consistent with grading substrate-specific downstream processes below the Sic1/G1/S axis. The cached record of the founding Sic1 paper is abstract-only and foregrounds cdc34 and the G1/S role; the curator read the full text, in which the cdc4 sic1 double-mutant behaviour underlies the G2/M inference, and the same conclusion was reached explicitly by Goh and Surana (PMID:10409741). Deferring to SGD on the genetic-interaction evidence. Supporting Evidence: PMID:7954792 cdc34 mutants cannot enter S phase because they fail to destroy p40SIC1, which is a potent inhibitor of Clb but not Cln forms of the Cdc28 kinase. PMID:10409741 lacking the CDC4 gene are arrested both at G(1)/S and at G(2)/M |
| GO:0000086 G2/M transition of mitotic cell cycle | IMP PMID:10409741 Cdc4, a protein required for the onset of S phase, serves an... | KEEP AS NON CORE | Summary: Cdc4 has a second, mechanistically less-defined role at the G2/M transition: cdc4 mutants relieved of their Sic1-dependent G1 block by SIC1 deletion arrest before anaphase, and that preanaphase arrest is relieved by deleting PDS1. Reason: The G2/M requirement is genuine (cdc4-delta sic1-delta and cdc4-12 sic1-delta cells arrest at G2/M, and cdc4 alleles suppress cdc20-1), but the substrate through which SCF(Cdc4) acts here has not been identified, and it is a second role rather than the defining function of the adaptor. Kept as non-core, consistent with grading substrate-specific downstream processes below the Sic1/G1/S axis. This is the primary paper: cdc4-delta cells arrest at both G1/S and G2/M, the G2/M arrest persists after SIC1 deletion, and it is relieved by PDS1 deletion, suggesting a link to Pds1 turnover that remains unresolved. Supporting Evidence: PMID:10409741 lacking the CDC4 gene are arrested both at G(1)/S and at G(2)/M PMID:10409741 cdc4-12 mutant is relieved by the deletion of PDS1 PMID:10409741 suggests that the Cdc4 function in G 2 /M may be linked to the degradation of Pds1 |
| GO:0000086 G2/M transition of mitotic cell cycle | NAS PMID:14747994 Functional interaction of 13 yeast SCF complexes with a set ... | KEEP AS NON CORE | Summary: Cdc4 has a second, mechanistically less-defined role at the G2/M transition: cdc4 mutants relieved of their Sic1-dependent G1 block by SIC1 deletion arrest before anaphase, and that preanaphase arrest is relieved by deleting PDS1. Reason: The G2/M requirement is genuine (cdc4-delta sic1-delta and cdc4-12 sic1-delta cells arrest at G2/M, and cdc4 alleles suppress cdc20-1), but the substrate through which SCF(Cdc4) acts here has not been identified, and it is a second role rather than the defining function of the adaptor. Kept as non-core, consistent with grading substrate-specific downstream processes below the Sic1/G1/S axis. The cited in vitro E2 survey does not itself address G2/M in its abstract; the author statement rests on the earlier genetic work (PMID:10409741), which is where the evidence lies. Supporting Evidence: PMID:10409741 lacking the CDC4 gene are arrested both at G(1)/S and at G(2)/M PMID:14747994 ubiquitination of Sic1 by the reconstituted SCF(Cdc4) complex was specifically |
| GO:0000472 endonucleolytic cleavage to generate mature 5'-end of SSU-rRNA from (SSU-rRNA, 5.8S rRNA, LSU-rRNA) | IBA GO_REF:0000033 | REMOVE | Summary: IBA transfer of an SSU-rRNA processing term to Cdc4 from a PANTHER node seeded by the SSU-processome protein Utp13; Cdc4 is an F-box SCF substrate receptor with no role in ribosome biogenesis. Reason: This IBA descends from PANTHER:PTN000457905, a node of the PLAA/WD40 family PTHR19849 whose IBD for this term was seeded on 2020-02-27 by a single S. cerevisiae SSU-processome protein, SGD:S000004212 (UTP13). The node groups Cdc4 with beta-propeller proteins of unrelated function rather than with the F-box branch: Cdc4 is an F-box/WD40 SCF substrate receptor with no reported association with the U3 snoRNP, the 90S preribosome or rRNA processing in more than forty years of study, its beta-propeller is the phosphodegron-binding surface, and its human ortholog FBXW7 receives adaptor activity at a separate node (PTN008571532). The argument is with the node placement, not with the single-donor count. Removed as an over-propagated family-level inference. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000457905 · PTN000457905 SUPPORTS SOURCE BUT NOT TARGET PTHR19849 (PLAA/WD40 family) node that groups the F-box protein Cdc4 with SSU-processome WD40 proteins; the ribosome-biogenesis IBDs on it are seeded only by UTP13. SGD:S000004212 · UTP13 SUPPORTS SOURCE BUT NOT TARGET Utp13 is a bona fide U3 snoRNP/90S preribosome WD40 protein; the evidence is sound for Utp13 but does not transfer to an F-box substrate receptor. Supporting Evidence: file:yeast/CDC4/CDC4-deep-research-falcon.md Cdc4 is best annotated as the **phosphorylation-dependent substrate receptor of the SCF^Cdc4 E3 ubiquitin-ligase complex**. PMID:9346238 Skp1 functions as the receptor that selectively binds phosphorylated Sic1. |
| GO:0000480 endonucleolytic cleavage in 5'-ETS of tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) | IBA GO_REF:0000033 | REMOVE | Summary: IBA transfer of an SSU-rRNA processing term to Cdc4 from a PANTHER node seeded by the SSU-processome protein Utp13; Cdc4 is an F-box SCF substrate receptor with no role in ribosome biogenesis. Reason: This IBA descends from PANTHER:PTN000457905, a node of the PLAA/WD40 family PTHR19849 whose IBD for this term was seeded on 2020-02-27 by a single S. cerevisiae SSU-processome protein, SGD:S000004212 (UTP13). The node groups Cdc4 with beta-propeller proteins of unrelated function rather than with the F-box branch: Cdc4 is an F-box/WD40 SCF substrate receptor with no reported association with the U3 snoRNP, the 90S preribosome or rRNA processing in more than forty years of study, its beta-propeller is the phosphodegron-binding surface, and its human ortholog FBXW7 receives adaptor activity at a separate node (PTN008571532). The argument is with the node placement, not with the single-donor count. Removed as an over-propagated family-level inference. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000457905 · PTN000457905 SUPPORTS SOURCE BUT NOT TARGET PTHR19849 (PLAA/WD40 family) node that groups the F-box protein Cdc4 with SSU-processome WD40 proteins; the ribosome-biogenesis IBDs on it are seeded only by UTP13. SGD:S000004212 · UTP13 SUPPORTS SOURCE BUT NOT TARGET Utp13 is a bona fide U3 snoRNP/90S preribosome WD40 protein; the evidence is sound for Utp13 but does not transfer to an F-box substrate receptor. Supporting Evidence: file:yeast/CDC4/CDC4-deep-research-falcon.md Cdc4 is best annotated as the **phosphorylation-dependent substrate receptor of the SCF^Cdc4 E3 ubiquitin-ligase complex**. PMID:9346238 Skp1 functions as the receptor that selectively binds phosphorylated Sic1. |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:9346239 A complex of Cdc4p, Skp1p, and Cdc53p/cullin catalyzes ubiqu... | ACCEPT | Summary: As the substrate-recognition subunit of SCF(Cdc4), Cdc4 contributes to the ubiquitin ligase activity of the complex; the catalytic ubiquitin transfer is performed by Cdc34 docked on the Cdc53-Hrt1 core. Reason: Accepted on the contributes_to claim as seeded: E3 activity is a property of the assembled SCF(Cdc4) complex, and Cdc4 supplies the substrate-recognition arm without which the reconstituted complex has no substrate-directed activity. The molecular function of the subunit itself is best described as ubiquitin-like ligase-substrate adaptor activity (GO:1990756), which is proposed as the replacement for the bare protein-binding rows and used in core_functions. The reconstitution paper shows that Cdc4, Cdc53 and Skp1 assemble into an E3 that, with E1, Cdc34 and ubiquitin, ubiquitinates phospho-Sic1, and that the Cdc4/Skp1 subcomplex is the substrate-binding part. Supporting Evidence: PMID:9346239 When mixed together, SCFCdc4p subunits, E1 enzyme, the E2 enzyme Cdc34p, and ubiquitin are sufficient to reconstitute ubiquitination of Cdk-phosphorylated Sic1p. PMID:9346239 Phosphorylated Sic1p substrate is specifically targeted for ubiquitination by binding to a Cdc4p/Skp1p subcomplex. file:yeast/CDC4/CDC4-deep-research-falcon.md Thus, **Cdc4 selects substrates and orients them for ubiquitination; Cdc34 performs ubiquitin transfer**. |
| GO:0005515 protein binding | IPI PMID:10688190 A comprehensive analysis of protein-protein interactions in ... | REMOVE | Summary: Skp1 interaction recorded in the proteome-wide two-hybrid screen of Uetz et al. Reason: High-throughput two-hybrid record; the Cdc4-Skp1 F-box interaction is characterised in the focused papers (PMID:8706131, PMID:9499404) and its functional meaning is recorded there. Bare protein binding carries no functional information about Cdc4, so the row is removed as uninformative; removal does not mean the reported interaction is false, and the SCF(Cdc4) membership it reflects is captured by the GO:0019005 annotations. Supporting Evidence: PMID:10688190 detection of 957 putative interactions involving 1,004 S. cerevisiae proteins |
| GO:0005515 protein binding | IPI PMID:11500370 Cic1, an adaptor protein specifically linking the 26S protea... | REMOVE | Summary: Cdc4 is bound by Cic1, a 26S proteasome-associated adaptor that channels Cdc4 (and Grr1) to the proteasome for its own degradation; Cdc4 is the substrate in this encounter. Reason: Removal reflects the term, not the data. In the Cic1-Cdc4 interaction Cdc4 is the protein being delivered to the proteasome, not the agent, so no Cdc4 activity is defined; the biology (turnover of the F-box protein) belongs on Cic1 and is noted for the ubiquitin-binding row. Bare protein binding carries no functional information about Cdc4 and is removed as uninformative; the interaction itself is not disputed and is retained in UniProt. Supporting Evidence: PMID:11500370 proteins Cdc4 and Grr1, substrate recognition subunits of the SCF complex PMID:11500370 interacts in vitro and in vivo with Cdc4, suggesting a function as a new kind of |
| GO:0005515 protein binding | IPI PMID:11805837 Systematic identification of protein complexes in Saccharomy... | REMOVE | Summary: Skp1 co-purification in the systematic mass-spectrometry survey of yeast protein complexes. Reason: Proteome-scale affinity-purification record whose cached entry is title-only; SCF(Cdc4) membership is established by the focused reconstitution work and recorded under GO:0019005. Bare protein binding carries no functional information about Cdc4, so the row is removed as uninformative; removal does not mean the reported interaction is false, and the SCF(Cdc4) membership it reflects is captured by the GO:0019005 annotations. |
| GO:0005515 protein binding | IPI PMID:14747994 Functional interaction of 13 yeast SCF complexes with a set ... | MODIFY | Summary: Cdc4 binds Skp1 within the reconstituted, purified SCF(Cdc4) complex that ubiquitinates Sic1 with Cdc34 or Ubc4. Reason: The informative function behind this interaction is Cdc4 acting as the F-box adaptor that bridges the Skp1-Cdc53 core of SCF to its phosphorylated substrates, i.e. ubiquitin-like ligase-substrate adaptor activity (GO:1990756); bare protein binding does not capture it. Resolved rather than removed because the cited study is a focused characterisation of the Skp1-Cdc4 (F-box) interaction, and complex membership itself is already recorded under GO:0019005. Here the Skp1-Cdc4 assembly is part of a purified complex shown to be active on Sic1. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:14747994 ubiquitination of Sic1 by the reconstituted SCF(Cdc4) complex was specifically PMID:14747994 catalyzed by two of the five E2 enzymes tested in vitro; Cdc34 and Ubc4 |
| GO:0005515 protein binding | IPI PMID:15448699 Hog1 mediates cell-cycle arrest in G1 phase by the dual targ... | MODIFY | Summary: Cdc4 recognises phosphorylated Sic1, its principal substrate; in the Hog1 osmostress paper the Cdc4-Sic1 interaction is the step antagonised when Hog1 phosphorylates Sic1 Thr173 and stabilises it. Reason: The informative function is Cdc4 acting as the substrate-recognition adaptor that brings a phosphodegron-bearing substrate to the SCF (Skp1-Cdc53-Hrt1) ligase, i.e. ubiquitin-like ligase-substrate adaptor activity (GO:1990756); bare protein binding does not capture it. The cached record is abstract-only, so the specific Cdc4 experiment cannot be checked here, but the curator read the full text and phospho-Sic1 recognition by Cdc4 is independently established by reconstitution and by direct binding measurements (PMID:9346238, PMID:19008353). Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:15448699 Hog1 interacts physically with Sic1 in vivo and in PMID:15448699 Sic1 stabilization and inhibition of cell-cycle progression PMID:19008353 The disordered cyclin-dependent kinase (CDK) inhibitor Sic1 interacts with a single site on its receptor Cdc4 only upon phosphorylation of its multiple dispersed CDK sites. |
| GO:0005515 protein binding | IPI PMID:17954914 The SCFCdc4 ubiquitin ligase regulates calcineurin signaling... | MODIFY | Summary: Cdc4 recognises Mck1-phosphorylated Rcn1, the calcineurin inhibitor, and SCF(Cdc4) targets it for degradation, thereby relieving calcineurin inhibition. Reason: The informative function is Cdc4 acting as the substrate-recognition adaptor that brings a phosphodegron-bearing substrate to the SCF (Skp1-Cdc53-Hrt1) ligase, i.e. ubiquitin-like ligase-substrate adaptor activity (GO:1990756); bare protein binding does not capture it. Full text cached: phosphorylated Rcn1 is degraded through SCF(Cdc4) in a Mck1-dependent manner, a canonical GSK-3-primed phosphodegron substrate. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:17954914 phosphorylation of yeast RCN, Rcn1, triggers degradation through the SCF(Cdc4) PMID:17954914 SCF(Cdc4)-dependent degradation required phosphorylation of Rcn1 by Mck1, a |
| GO:0005515 protein binding | IPI PMID:17960736 Interactome and interface protocol (2IP): a novel strategy f... | REMOVE | Summary: Skp1 crosslink detected while validating the 2IP topology-mapping protocol on the yeast SCF complex. Reason: Methodological benchmark interaction; it adds no functional information beyond the focused Skp1-binding rows and GO:0019005. Bare protein binding carries no functional information about Cdc4, so the row is removed as uninformative; removal does not mean the reported interaction is false, and the SCF(Cdc4) membership it reflects is captured by the GO:0019005 annotations. Supporting Evidence: PMID:17960736 quaternary structure of components of the yeast Skp1-Cdc53/Cullin-F box (SCF) |
| GO:0005515 protein binding | IPI PMID:18719252 High-quality binary protein interaction map of the yeast int... | REMOVE | Summary: Skp1 interaction from the high-quality binary yeast interactome (Y2H) map. Reason: Proteome-scale binary interaction map; the Cdc4-Skp1 interaction is characterised in the focused F-box papers. Bare protein binding carries no functional information about Cdc4, so the row is removed as uninformative; removal does not mean the reported interaction is false, and the SCF(Cdc4) membership it reflects is captured by the GO:0019005 annotations. |
| GO:0005515 protein binding | IPI PMID:18787112 A refined two-hybrid system reveals that SCF(Cdc4)-dependent... | MODIFY | Summary: Rcn1 recovered as an SCF(Cdc4) substrate in the refined two-hybrid screen that stabilises substrates during screening (the same paper identified Swi5). Reason: The informative function is Cdc4 acting as the substrate-recognition adaptor that brings a phosphodegron-bearing substrate to the SCF (Skp1-Cdc53-Hrt1) ligase, i.e. ubiquitin-like ligase-substrate adaptor activity (GO:1990756); bare protein binding does not capture it. Full text cached: RCN1 was among the clones recovered, and the authors list Rcn1 with Swi5 and Spo74 as SCF(Cdc4) substrates, consistent with their earlier degradation study (PMID:17954914). Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:18787112 We identified Swi5, Rcn1, and Spo74 as substrates of the SCF Cdc4 complex. PMID:17954914 phosphorylation of yeast RCN, Rcn1, triggers degradation through the SCF(Cdc4) |
| GO:0005515 protein binding | IPI PMID:18787112 A refined two-hybrid system reveals that SCF(Cdc4)-dependent... | MODIFY | Summary: Sic1-Cdc4 interaction used as the positive control of the refined two-hybrid screen; it is abolished by sic1 phosphorylation-site mutations that block Cdc28/Pho85 phosphorylation. Reason: The informative function is Cdc4 acting as the substrate-recognition adaptor that brings a phosphodegron-bearing substrate to the SCF (Skp1-Cdc53-Hrt1) ligase, i.e. ubiquitin-like ligase-substrate adaptor activity (GO:1990756); bare protein binding does not capture it. Full text cached: the phosphorylation dependence of the Sic1-Cdc4 two-hybrid signal is exactly the phosphodegron-recognition step. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:18787112 Such phosphorylation enables Sic1-Cdc4 interaction required for ubiquitination of Sic1. PMID:18787112 identified Swi5 as a substrate of the SCF(Cdc4) complex |
| GO:0005515 protein binding | IPI PMID:19008353 Dynamic equilibrium engagement of a polyvalent ligand with a... | MODIFY | Summary: Direct, quantitative characterisation of the Cdc4-phospho-Sic1 interaction by NMR and fluorescence: multiply phosphorylated Sic1 binds a single site on Cdc4 in a dynamic equilibrium of suboptimal phosphodegrons, with no binding of unphosphorylated Sic1. Reason: The informative function is Cdc4 acting as the substrate-recognition adaptor that brings a phosphodegron-bearing substrate to the SCF (Skp1-Cdc53-Hrt1) ligase, i.e. ubiquitin-like ligase-substrate adaptor activity (GO:1990756); bare protein binding does not capture it. This is the most direct biophysical evidence for phosphodegron recognition by the Cdc4 WD40 propeller and explains the ultrasensitive, threshold-like response to Sic1 phosphorylation. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:19008353 The disordered cyclin-dependent kinase (CDK) inhibitor Sic1 interacts with a single site on its receptor Cdc4 only upon phosphorylation of its multiple dispersed CDK sites. PMID:19008353 targets Sic1 to the SCF Cdc4 ubiquitin ligase, resulting in Sic1 ubiquitination and degradation by the proteasome |
| GO:0005515 protein binding | IPI PMID:19882662 Remodeling of the SCF complex-mediated ubiquitination system... | REMOVE | Summary: Co-purification recorded in the quantitative proteomic survey of F-box protein composition of SCF complexes purified en masse from log- and post-diauxic-phase cells. (partner Skp1). Reason: Proteome-scale stoichiometry survey; Skp1 engagement is characterised in the focused F-box papers. Bare protein binding carries no functional information about Cdc4, so the row is removed as uninformative; removal does not mean the reported interaction is false, and the SCF(Cdc4) membership it reflects is captured by the GO:0019005 annotations. Supporting Evidence: PMID:19882662 relative quantification of F-box proteins in the SCF PMID:19882662 component responsible for substrate recognition, thereby defining the function |
| GO:0005515 protein binding | IPI PMID:19882662 Remodeling of the SCF complex-mediated ubiquitination system... | REMOVE | Summary: Co-purification recorded in the quantitative proteomic survey of F-box protein composition of SCF complexes purified en masse from log- and post-diauxic-phase cells. (partner Hrt1). Reason: Proteome-scale survey; the Cdc4-Hrt1 association is indirect, mediated through Skp1 and the Cdc53 scaffold, and is captured by SCF complex membership (GO:0019005). Bare protein binding carries no functional information about Cdc4, so the row is removed as uninformative; removal does not mean the reported interaction is false, and the SCF(Cdc4) membership it reflects is captured by the GO:0019005 annotations. Supporting Evidence: PMID:19882662 relative quantification of F-box proteins in the SCF |
| GO:0005515 protein binding | IPI PMID:19882662 Remodeling of the SCF complex-mediated ubiquitination system... | REMOVE | Summary: Co-purification recorded in the quantitative proteomic survey of F-box protein composition of SCF complexes purified en masse from log- and post-diauxic-phase cells. (partner Cdc53). Reason: Proteome-scale survey; the Cdc53 scaffold interaction is characterised directly by Patton et al. (PMID:9499404), where it is resolved to cullin family protein binding. Bare protein binding carries no functional information about Cdc4, so the row is removed as uninformative; removal does not mean the reported interaction is false, and the SCF(Cdc4) membership it reflects is captured by the GO:0019005 annotations. Supporting Evidence: PMID:19882662 relative quantification of F-box proteins in the SCF |
| GO:0005515 protein binding | IPI PMID:23267104 Proteome-wide protein interaction measurements of bacterial ... | REMOVE | Summary: Interaction recorded in a microfluidic protein-interaction study whose subject is Streptococcus pneumoniae proteins of unknown function; the cached text does not mention Cdc4, so the yeast SCF pair was presumably used as an assay control. (partner Skp1). Reason: Methodological/high-throughput record outside the biology of this gene; the Skp1 interaction is characterised in the focused F-box papers. Bare protein binding carries no functional information about Cdc4, so the row is removed as uninformative; removal does not mean the reported interaction is false, and the SCF(Cdc4) membership it reflects is captured by the GO:0019005 annotations. Supporting Evidence: PMID:23267104 Binary protein--protein interactions in the model organism |
| GO:0005515 protein binding | IPI PMID:23267104 Proteome-wide protein interaction measurements of bacterial ... | REMOVE | Summary: Interaction recorded in a microfluidic protein-interaction study whose subject is Streptococcus pneumoniae proteins of unknown function; the cached text does not mention Cdc4, so the yeast SCF pair was presumably used as an assay control. (partner Hrt1). Reason: Methodological/high-throughput record; the Cdc4-Hrt1 association is indirect (via Skp1 and Cdc53) and is captured by SCF complex membership (GO:0019005). Bare protein binding carries no functional information about Cdc4, so the row is removed as uninformative; removal does not mean the reported interaction is false, and the SCF(Cdc4) membership it reflects is captured by the GO:0019005 annotations. Supporting Evidence: PMID:23267104 Binary protein--protein interactions in the model organism |
| GO:0005515 protein binding | IPI PMID:37968396 The social and structural architecture of the yeast protein ... | REMOVE | Summary: Cdc53 co-enrichment in the proteome-wide affinity-enrichment mass-spectrometry map of the yeast interactome. Reason: Proteome-scale interactome resource; the Cdc4-Cdc53 scaffold interaction is characterised directly by Patton et al. (PMID:9499404). Bare protein binding carries no functional information about Cdc4, so the row is removed as uninformative; removal does not mean the reported interaction is false, and the SCF(Cdc4) membership it reflects is captured by the GO:0019005 annotations. Supporting Evidence: PMID:37968396 The 4,159 pull-downs generated a highly structured network of 3,927 proteins |
| GO:0005515 protein binding | IPI PMID:8706131 SKP1 connects cell cycle regulators to the ubiquitin proteol... | MODIFY | Summary: The founding F-box paper: Skp1, isolated as a suppressor of cdc4 mutants, binds Cdc4 directly through the F-box motif and is required for ubiquitin-mediated proteolysis of Sic1. Reason: The informative function behind this interaction is Cdc4 acting as the F-box adaptor that bridges the Skp1-Cdc53 core of SCF to its phosphorylated substrates, i.e. ubiquitin-like ligase-substrate adaptor activity (GO:1990756); bare protein binding does not capture it. Resolved rather than removed because the cited study is a focused characterisation of the Skp1-Cdc4 (F-box) interaction, and complex membership itself is already recorded under GO:0019005. This paper defined the F-box as the Skp1-binding motif and showed that Skp1 links Cdc4 to the proteolysis machinery. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:8706131 directly binds Skp2p, cyclin F, and Cdc4p through a PMID:8706131 novel structural motif called the F-box PMID:8706131 proteolysis of Cin2p, Clb5p, and the Cdk inhibitor Sic1p |
| GO:0005515 protein binding | IPI PMID:9499404 Cdc53 is a scaffold protein for multiple Cdc34/Skp1/F-box pr... | MODIFY | Summary: Cdc4 forms a Skp1-containing complex on the Cdc53 scaffold; F-box proteins confer functional specificity, with Cdc4 specific for Sic1 degradation. Reason: The informative function behind this interaction is Cdc4 acting as the F-box adaptor that bridges the Skp1-Cdc53 core of SCF to its phosphorylated substrates, i.e. ubiquitin-like ligase-substrate adaptor activity (GO:1990756); bare protein binding does not capture it. Resolved rather than removed because the cited study is a focused characterisation of the Skp1-Cdc4 (F-box) interaction, and complex membership itself is already recorded under GO:0019005. Two-hybrid and co-immunoprecipitation data here establish the Cdc53-Skp1-Cdc4 arrangement and the substrate specificity Cdc4 brings to it. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:9499404 Cdc53 forms distinct complexes with Skp1, Cdc34, and the F-box proteins Cdc4, Grr1, and Met30 in vivo PMID:9499404 Cdc4 is specific for degradation of Sic1 |
| GO:0005515 protein binding | IPI PMID:9499404 Cdc53 is a scaffold protein for multiple Cdc34/Skp1/F-box pr... | MODIFY | Summary: Cdc4 associates with the cullin Cdc53, which acts as a scaffold with separate binding sites for Skp1/F-box proteins and the E2 Cdc34. Reason: The informative function is binding of the cullin scaffold (through Skp1), for which cullin family protein binding (GO:0097602) is the specific term, as used for the human SKP2-CUL1 rows; bare protein binding is uninformative. Full text cached: Cdc53 forms distinct complexes with Skp1, Cdc34 and the F-box proteins Cdc4, Grr1 and Met30. Proposed replacements: cullin family protein binding Supporting Evidence: PMID:9499404 Cdc53 serves as a scaffold protein that links Skp1/F-box proteins and Cdc34 PMID:9499404 Cdc53 forms distinct complexes with Skp1, Cdc34, and the F-box proteins Cdc4, Grr1, and Met30 in vivo |
| GO:0005634 nucleus | IDA PMID:11080155 Nuclear-specific degradation of Far1 is controlled by the lo... | ACCEPT | Summary: Cdc4 is exclusively nuclear (functional Cdc4-GFP, monopartite NLS in residues 1-106), which confines SCF(Cdc4)-dependent Far1 degradation to the nucleus. Reason: Core location, shown directly with a functional GFP fusion and by NLS mapping; a cytoplasm-forced Cdc4 fails to complement cdc4-1, showing that nuclear residence is required for the essential function. Consistent with the nuclear identity of the substrates (Sic1, Far1, Cdc6, Gcn4, Swi5, Ash1, Eco1). Supporting Evidence: PMID:11080155 whereas the F-box protein Cdc4 was exclusively nuclear PMID:11080155 Cdc4 is exclusively localized to the cell nucleus PMID:11080155 Cdc4 was unable to complement the growth defect of cdc4-1 cells |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic nucleus assignment from the UniProt subcellular-location annotation, which itself cites the Far1/Cdc4 localisation study. Reason: Agrees with the direct GFP and NLS evidence (PMID:11080155) and with the nuclear-fraction biochemistry of Choi et al. (PMID:2244914). Supporting Evidence: PMID:11080155 whereas the F-box protein Cdc4 was exclusively nuclear file:yeast/CDC4/CDC4-deep-research-falcon.md Cdc4 is principally a **nuclear protein** |
| GO:0005730 nucleolus | IBA GO_REF:0000033 | REMOVE | Summary: IBA transfer of nucleolar localisation to Cdc4 from a PANTHER node whose seeds are SSU-processome WD40 proteins (Utp13 and its homologs in other species). Reason: The nucleolus IBD on PANTHER:PTN000457905 (updated 2025-12-19) is seeded by S. cerevisiae UTP13 (SGD:S000004212) and by its plant, Candida, fission-yeast and trypanosome counterparts, all U3 snoRNP/90S preribosome components; the node sits in the PLAA/WD40 family PTHR19849 and groups Cdc4 with these beta-propeller proteins rather than with the F-box branch. Cdc4 is nuclear (functional GFP fusion, NLS mapping) with no reported nucleolar enrichment, and its substrates are nucleoplasmic and chromatin-bound cell-cycle and transcription regulators. As an is_active_in claim for a compartment where the protein has no demonstrated function, this is an over-propagated compartment transfer and is removed; the direct nucleus annotations stand. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN000457905 · PTN000457905 SUPPORTS SOURCE BUT NOT TARGET PTHR19849 (PLAA/WD40 family) node that groups the F-box protein Cdc4 with SSU-processome WD40 proteins; the ribosome-biogenesis IBDs on it are seeded only by UTP13. The nucleolus IBD on this node also lists AT5G16750, CGD:CAL0000184822, PomBase:SPCC16A11.02, UniProtKB:Q12788 and UniProtKB:Q387K5, which are not traced individually here. SGD:S000004212 · UTP13 SUPPORTS SOURCE BUT NOT TARGET Utp13 is a bona fide U3 snoRNP/90S preribosome WD40 protein; the evidence is sound for Utp13 but does not transfer to an F-box substrate receptor. Supporting Evidence: PMID:11080155 whereas the F-box protein Cdc4 was exclusively nuclear file:yeast/CDC4/CDC4-deep-research-falcon.md Cdc4 is principally a **nuclear protein** |
| GO:0006511 ubiquitin-dependent protein catabolic process | IDA PMID:14747994 Functional interaction of 13 yeast SCF complexes with a set ... | MODIFY | Summary: Cdc4 mediates ubiquitin-dependent proteolysis as the substrate receptor of the SCF(Cdc4) ligase that ubiquitinates phosphorylated Sic1 for proteasomal destruction. Reason: The biology is core and correct, but the term is the generic parent of SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146), which is the precise statement for an F-box receptor and is already carried by this gene from the two reconstitution papers. Modified to the specific child; the essence of the annotation is unchanged. Kus et al. reconstituted 13 SCF complexes and showed Sic1 ubiquitination by purified SCF(Cdc4) with Cdc34 or Ubc4. Proposed replacements: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process Supporting Evidence: PMID:14747994 ubiquitination of Sic1 by the reconstituted SCF(Cdc4) complex was specifically PMID:14747994 catalyzed by two of the five E2 enzymes tested in vitro; Cdc34 and Ubc4 |
| GO:0006511 ubiquitin-dependent protein catabolic process | IDA PMID:9346238 F-box proteins are receptors that recruit phosphorylated sub... | MODIFY | Summary: Cdc4 mediates ubiquitin-dependent proteolysis as the substrate receptor of the SCF(Cdc4) ligase that ubiquitinates phosphorylated Sic1 for proteasomal destruction. Reason: The biology is core and correct, but the term is the generic parent of SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146), which is the precise statement for an F-box receptor and is already carried by this gene from the two reconstitution papers. Modified to the specific child; the essence of the annotation is unchanged. Skowyra et al. reconstituted Sic1 ubiquitination with recombinant Skp1, Cdc53, Cdc4, Cdc34 and E1, and showed that Cdc4-Skp1 is the receptor for phosphorylated Sic1. Proposed replacements: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process Supporting Evidence: PMID:9346238 complex, SCFCdc4, which functions as a Sic1 ubiquitin-ligase (E3) in combination PMID:9346238 Skp1 functions as the receptor that selectively binds phosphorylated Sic1. |
| GO:0006511 ubiquitin-dependent protein catabolic process | IDA PMID:9346239 A complex of Cdc4p, Skp1p, and Cdc53p/cullin catalyzes ubiqu... | MODIFY | Summary: Cdc4 mediates ubiquitin-dependent proteolysis as the substrate receptor of the SCF(Cdc4) ligase that ubiquitinates phosphorylated Sic1 for proteasomal destruction. Reason: The biology is core and correct, but the term is the generic parent of SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146), which is the precise statement for an F-box receptor and is already carried by this gene from the two reconstitution papers. Modified to the specific child; the essence of the annotation is unchanged. Feldman et al. showed that SCF(Cdc4) subunits with E1, Cdc34 and ubiquitin suffice to ubiquitinate Cdk-phosphorylated Sic1. Proposed replacements: SCF-dependent proteasomal ubiquitin-dependent protein catabolic process Supporting Evidence: PMID:9346239 When mixed together, SCFCdc4p subunits, E1 enzyme, the E2 enzyme Cdc34p, and ubiquitin are sufficient to reconstitute ubiquitination of Cdk-phosphorylated Sic1p. PMID:9346239 Phosphorylated Sic1p substrate is specifically targeted for ubiquitination by binding to a Cdc4p/Skp1p subcomplex. |
| GO:0016363 nuclear matrix | IDA PMID:2244914 The CDC4 gene product is associated with the yeast nuclear s... | MARK AS OVER ANNOTATED | Summary: Cdc4 co-fractionated with two biochemical preparations of yeast nucleoskeletal proteins in a 1990 immunoblot study, interpreted as association with the nuclear skeleton. Reason: The nuclear localisation is correct and confirmed by later GFP work, but the specific nuclear-matrix claim rests on co-sedimentation with detergent/salt-resistant nuclear fractions before the SCF mechanism was known, and it has not been substantiated by any subsequent study; the modern picture is a soluble nuclear SCF substrate receptor that acts on nucleoplasmic and chromatin-bound substrates. Retained as an experimental record but marked as over-interpreting the fractionation evidence; the nucleus rows capture the location. Supporting Evidence: PMID:2244914 the CDC4 gene product localizes in the nucleus by two different biochemical PMID:2244914 includes the CDC4 gene product as a component of the yeast nuclear skeleton file:yeast/CDC4/CDC4-deep-research-falcon.md Cdc4 has also historically been associated with the nuclear skeleton, but the most defensible modern annotation is **nuclear SCF substrate receptor** |
| GO:0016567 protein ubiquitination | IDA PMID:23645675 Dynamic ubiquitination of the mitogen-activated protein kina... | ACCEPT | Summary: SCF(Cdc4) ubiquitinates the MAPKK Ste7 directly with purified components; this ubiquitination, opposed by the deubiquitinase Ubp3, tunes MAPK specificity (Fus3 versus Kss1) rather than simply destroying Ste7. Reason: Core process at the generic level: protein ubiquitination is what SCF(Cdc4) executes on every substrate, and this paper adds a directly demonstrated, non-canonical output in which the modification regulates signalling. The generic term is appropriate here because the Ste7 modification is not shown to be proteasome-directed; the degradative cases are captured by GO:0031146. Supporting Evidence: PMID:23645675 we demonstrate that SCF(Cdc4) ubiquitinates Ste7 directly PMID:23645675 Although SCF(Cdc4) is necessary for proper activation of the |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | ACCEPT | Summary: Electronic assignment of protein ubiquitination from the UniPathway protein-ubiquitination pathway mapping. Reason: Agrees with the reconstituted ubiquitination of Sic1 and Ste7 by SCF(Cdc4); a correct generic statement of the process the complex carries out. Supporting Evidence: PMID:9346239 When mixed together, SCFCdc4p subunits, E1 enzyme, the E2 enzyme Cdc34p, and ubiquitin are sufficient to reconstitute ubiquitination of Cdk-phosphorylated Sic1p. PMID:23645675 we demonstrate that SCF(Cdc4) ubiquitinates Ste7 directly |
| GO:0019005 SCF ubiquitin ligase complex | IDA PMID:14747994 Functional interaction of 13 yeast SCF complexes with a set ... | ACCEPT | Summary: Cdc4 is the F-box/WD40 substrate-receptor subunit of the SCF(Cdc4) ubiquitin ligase (Skp1-Cdc53-Hrt1-Cdc4), which with the E2 Cdc34 ubiquitinates phosphorylated Sic1. Reason: Core cellular component. Cdc4, Skp1 and Cdc53 co-purify as a complex that, with E1, Cdc34 and ubiquitin, is sufficient to ubiquitinate Cdk-phosphorylated Sic1; the F-box binds Skp1 and the Cdc53 scaffold links the Skp1-Cdc4 arm to Cdc34. Cdc4 has no activity outside this complex. Kus et al. reconstituted and purified SCF(Cdc4) among 13 SCF complexes and showed it is active on Sic1. Supporting Evidence: PMID:14747994 ubiquitination of Sic1 by the reconstituted SCF(Cdc4) complex was specifically PMID:14747994 at least eight of the purified SCF complexes clearly ubiquitinated |
| GO:0019005 SCF ubiquitin ligase complex | IDA PMID:9346238 F-box proteins are receptors that recruit phosphorylated sub... | ACCEPT | Summary: Cdc4 is the F-box/WD40 substrate-receptor subunit of the SCF(Cdc4) ubiquitin ligase (Skp1-Cdc53-Hrt1-Cdc4), which with the E2 Cdc34 ubiquitinates phosphorylated Sic1. Reason: Core cellular component. Cdc4, Skp1 and Cdc53 co-purify as a complex that, with E1, Cdc34 and ubiquitin, is sufficient to ubiquitinate Cdk-phosphorylated Sic1; the F-box binds Skp1 and the Cdc53 scaffold links the Skp1-Cdc4 arm to Cdc34. Cdc4 has no activity outside this complex. Skowyra et al. showed that Skp1, Cdc53 and Cdc4 form the SCFCdc4 complex that functions as the Sic1 E3 with Cdc34. Supporting Evidence: PMID:9346238 Skp1, Cdc53, and the F-box protein Cdc4 form a PMID:9346238 complex, SCFCdc4, which functions as a Sic1 ubiquitin-ligase (E3) in combination |
| GO:0019005 SCF ubiquitin ligase complex | IDA PMID:9346239 A complex of Cdc4p, Skp1p, and Cdc53p/cullin catalyzes ubiqu... | ACCEPT | Summary: Cdc4 is the F-box/WD40 substrate-receptor subunit of the SCF(Cdc4) ubiquitin ligase (Skp1-Cdc53-Hrt1-Cdc4), which with the E2 Cdc34 ubiquitinates phosphorylated Sic1. Reason: Core cellular component. Cdc4, Skp1 and Cdc53 co-purify as a complex that, with E1, Cdc34 and ubiquitin, is sufficient to ubiquitinate Cdk-phosphorylated Sic1; the F-box binds Skp1 and the Cdc53 scaffold links the Skp1-Cdc4 arm to Cdc34. Cdc4 has no activity outside this complex. Feldman et al. named the Cdc4-Cdc53-Skp1 assembly SCFCdc4 and reconstituted its activity. Supporting Evidence: PMID:9346239 We show here that Cdc4p, Cdc53p, and Skp1p assemble into a ubiquitin ligase complex named SCFCdc4p. PMID:9346239 When mixed together, SCFCdc4p subunits, E1 enzyme, the E2 enzyme Cdc34p, and ubiquitin are sufficient to reconstitute ubiquitination of Cdk-phosphorylated Sic1p. |
| GO:0019005 SCF ubiquitin ligase complex | IPI PMID:9346238 F-box proteins are receptors that recruit phosphorylated sub... | ACCEPT | Summary: Cdc4 is the F-box/WD40 substrate-receptor subunit of the SCF(Cdc4) ubiquitin ligase (Skp1-Cdc53-Hrt1-Cdc4), which with the E2 Cdc34 ubiquitinates phosphorylated Sic1. Physical-interaction row with Skp1 (SGD:S000002736). Reason: Core cellular component. Cdc4, Skp1 and Cdc53 co-purify as a complex that, with E1, Cdc34 and ubiquitin, is sufficient to ubiquitinate Cdk-phosphorylated Sic1; the F-box binds Skp1 and the Cdc53 scaffold links the Skp1-Cdc4 arm to Cdc34. Cdc4 has no activity outside this complex. The Skp1-Cdc4 interaction is the F-box contact that incorporates Cdc4 into the complex. Supporting Evidence: PMID:9346238 Skp1, Cdc53, and the F-box protein Cdc4 form a PMID:9346238 Skp1 functions as the receptor that selectively binds phosphorylated Sic1. |
| GO:0019005 SCF ubiquitin ligase complex | IPI PMID:9346239 A complex of Cdc4p, Skp1p, and Cdc53p/cullin catalyzes ubiqu... | ACCEPT | Summary: Cdc4 is the F-box/WD40 substrate-receptor subunit of the SCF(Cdc4) ubiquitin ligase (Skp1-Cdc53-Hrt1-Cdc4), which with the E2 Cdc34 ubiquitinates phosphorylated Sic1. Physical-interaction row with Cdc53 (SGD:S000002290). Reason: Core cellular component. Cdc4, Skp1 and Cdc53 co-purify as a complex that, with E1, Cdc34 and ubiquitin, is sufficient to ubiquitinate Cdk-phosphorylated Sic1; the F-box binds Skp1 and the Cdc53 scaffold links the Skp1-Cdc4 arm to Cdc34. Cdc4 has no activity outside this complex. Cdc53 is the cullin scaffold on which the Skp1-Cdc4 arm assembles. Supporting Evidence: PMID:9346239 We show here that Cdc4p, Cdc53p, and Skp1p assemble into a ubiquitin ligase complex named SCFCdc4p. PMID:9499404 Cdc53 serves as a scaffold protein that links Skp1/F-box proteins and Cdc34 |
| GO:0019005 SCF ubiquitin ligase complex | IPI PMID:9346239 A complex of Cdc4p, Skp1p, and Cdc53p/cullin catalyzes ubiqu... | ACCEPT | Summary: Cdc4 is the F-box/WD40 substrate-receptor subunit of the SCF(Cdc4) ubiquitin ligase (Skp1-Cdc53-Hrt1-Cdc4), which with the E2 Cdc34 ubiquitinates phosphorylated Sic1. Physical-interaction row with Skp1 (SGD:S000002736). Reason: Core cellular component. Cdc4, Skp1 and Cdc53 co-purify as a complex that, with E1, Cdc34 and ubiquitin, is sufficient to ubiquitinate Cdk-phosphorylated Sic1; the F-box binds Skp1 and the Cdc53 scaffold links the Skp1-Cdc4 arm to Cdc34. Cdc4 has no activity outside this complex. The phospho-Sic1-binding activity resides in the Cdc4/Skp1 subcomplex. Supporting Evidence: PMID:9346239 We show here that Cdc4p, Cdc53p, and Skp1p assemble into a ubiquitin ligase complex named SCFCdc4p. PMID:9346239 Phosphorylated Sic1p substrate is specifically targeted for ubiquitination by binding to a Cdc4p/Skp1p subcomplex. |
| GO:0030686 90S preribosome | IBA GO_REF:0000033 | REMOVE | Summary: IBA transfer of 90S preribosome membership to Cdc4 from a PANTHER node seeded by the SSU-processome protein Utp13. Reason: This IBA descends from PANTHER:PTN000457905, a node of the PLAA/WD40 family PTHR19849 whose IBD for this term was seeded on 2020-02-27 by a single S. cerevisiae SSU-processome protein, SGD:S000004212 (UTP13). The node groups Cdc4 with beta-propeller proteins of unrelated function rather than with the F-box branch: Cdc4 is an F-box/WD40 SCF substrate receptor with no reported association with the U3 snoRNP, the 90S preribosome or rRNA processing in more than forty years of study, its beta-propeller is the phosphodegron-binding surface, and its human ortholog FBXW7 receives adaptor activity at a separate node (PTN008571532). The argument is with the node placement, not with the single-donor count. Removed as an over-propagated family-level inference. Cdc4 is a subunit of the nuclear SCF ubiquitin ligase complex (GO:0019005, GO:0043224), not of a preribosomal particle. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN000457905 · PTN000457905 SUPPORTS SOURCE BUT NOT TARGET PTHR19849 (PLAA/WD40 family) node that groups the F-box protein Cdc4 with SSU-processome WD40 proteins; the ribosome-biogenesis IBDs on it are seeded only by UTP13. SGD:S000004212 · UTP13 SUPPORTS SOURCE BUT NOT TARGET Utp13 is a bona fide U3 snoRNP/90S preribosome WD40 protein; the evidence is sound for Utp13 but does not transfer to an F-box substrate receptor. Supporting Evidence: file:yeast/CDC4/CDC4-deep-research-falcon.md Cdc4 is best annotated as the **phosphorylation-dependent substrate receptor of the SCF^Cdc4 E3 ubiquitin-ligase complex**. PMID:9346239 We show here that Cdc4p, Cdc53p, and Skp1p assemble into a ubiquitin ligase complex named SCFCdc4p. |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IDA PMID:9346238 F-box proteins are receptors that recruit phosphorylated sub... | ACCEPT | Summary: Cdc4 targets phosphorylated substrates (Sic1, Far1, Cdc6, Gcn4, Swi5, Rcn1, Ash1, Eco1 and others) for SCF-dependent ubiquitination and proteasomal degradation. Reason: Core biological process: this is what SCF(Cdc4) does, demonstrated by reconstituted ubiquitination of phospho-Sic1, by cdc4 loss-of-function stabilisation of Sic1, Far1, Cdc6, Gcn4, Swi5, Rcn1 and Ash1, and by degron mutagenesis. Cdc4 performs the recognition step, so the participation test is met. Skowyra et al. established Cdc4-Skp1 as the phospho-substrate receptor. Supporting Evidence: PMID:9346238 Skp1 functions as the receptor that selectively binds phosphorylated Sic1. PMID:9346238 complex, SCFCdc4, which functions as a Sic1 ubiquitin-ligase (E3) in combination PMID:11080155 ubiquitylates Far1 in the nucleus, which in turn targets the multi-ubiquitylated |
| GO:0031146 SCF-dependent proteasomal ubiquitin-dependent protein catabolic process | IDA PMID:9346239 A complex of Cdc4p, Skp1p, and Cdc53p/cullin catalyzes ubiqu... | ACCEPT | Summary: Cdc4 targets phosphorylated substrates (Sic1, Far1, Cdc6, Gcn4, Swi5, Rcn1, Ash1, Eco1 and others) for SCF-dependent ubiquitination and proteasomal degradation. Reason: Core biological process (see the companion row): Feldman et al. reconstituted SCF(Cdc4)-Cdc34-dependent ubiquitination of Cdk-phosphorylated Sic1, the step that commits Sic1 to proteasomal destruction at G1/S. Supporting Evidence: PMID:9346239 When mixed together, SCFCdc4p subunits, E1 enzyme, the E2 enzyme Cdc34p, and ubiquitin are sufficient to reconstitute ubiquitination of Cdk-phosphorylated Sic1p. PMID:9346239 Phosphorylated Sic1p substrate is specifically targeted for ubiquitination by binding to a Cdc4p/Skp1p subcomplex. file:yeast/CDC4/CDC4-deep-research-falcon.md Sic1 destruction releases S-phase Clb–Cdk activity, promoting the G1/S transition and DNA-replication initiation. |
| GO:0034511 U3 snoRNA binding | IBA GO_REF:0000033 | REMOVE | Summary: IBA transfer of U3 snoRNA binding to Cdc4 from a PANTHER node seeded by the SSU-processome protein Utp13. Reason: This IBA descends from PANTHER:PTN000457905, a node of the PLAA/WD40 family PTHR19849 whose IBD for this term was seeded on 2020-02-27 by a single S. cerevisiae SSU-processome protein, SGD:S000004212 (UTP13). The node groups Cdc4 with beta-propeller proteins of unrelated function rather than with the F-box branch: Cdc4 is an F-box/WD40 SCF substrate receptor with no reported association with the U3 snoRNP, the 90S preribosome or rRNA processing in more than forty years of study, its beta-propeller is the phosphodegron-binding surface, and its human ortholog FBXW7 receives adaptor activity at a separate node (PTN008571532). The argument is with the node placement, not with the single-donor count. Removed as an over-propagated family-level inference. The Cdc4 propeller binds phosphodegron peptides and ubiquitin; no nucleic-acid binding has been reported. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN000457905 · PTN000457905 SUPPORTS SOURCE BUT NOT TARGET PTHR19849 (PLAA/WD40 family) node that groups the F-box protein Cdc4 with SSU-processome WD40 proteins; the ribosome-biogenesis IBDs on it are seeded only by UTP13. SGD:S000004212 · UTP13 SUPPORTS SOURCE BUT NOT TARGET Utp13 is a bona fide U3 snoRNP/90S preribosome WD40 protein; the evidence is sound for Utp13 but does not transfer to an F-box substrate receptor. Supporting Evidence: PMID:23314252 Cdc4 displays a preference for diphosphorylated degrons, often grouped in clusters PMID:21070969 by the F box protein Cdc4 promotes its autoubiquitination and turnover |
| GO:0043130 ubiquitin binding | IDA PMID:21070969 WD40 repeat propellers define a ubiquitin-binding domain tha... | KEEP AS NON CORE | Summary: The Cdc4 WD40 beta-propeller binds ubiquitin through its top surface, at a site spatially separate from the phosphodegron pocket; propeller mutants defective in ubiquitin binding are stabilised, so ubiquitin binding promotes Cdc4 autoubiquitination and turnover. Reason: A direct, well-controlled molecular function of the protein itself, but it governs the F-box protein's own turnover rather than substrate selection, and phosphodegron binding is unaffected by the ubiquitin-site mutants. Kept as a non-core regulatory activity alongside the adaptor function. Supporting Evidence: PMID:21070969 by the F box protein Cdc4 promotes its autoubiquitination and turnover PMID:21070969 mutations that diminished Ub binding extended the half-life of Cdc4, suggesting that Ub binding fosters the ubiquitination and degradation of Cdc4 PMID:21070969 phosphodegron peptides that bind Fbw7 and Cdc4 did not diminish Ub binding by the |
| GO:0043224 nuclear SCF ubiquitin ligase complex | IDA PMID:11080155 Nuclear-specific degradation of Far1 is controlled by the lo... | ACCEPT | Summary: Cdc4 is the exclusively nuclear F-box subunit that defines the nuclear SCF(Cdc4) complex, whereas Cdc53, Skp1, Cdc34 and Hrt1 are found in both nucleus and cytoplasm. Reason: Core cellular component and the most precise statement of where the complex acts: nuclear-restricted Cdc4 confines Far1 ubiquitylation to the nucleus, and only nuclear Cdc4 supports viability. Duplicates the parent GO:0019005 rows at a more informative level. Supporting Evidence: PMID:11080155 whereas the F-box protein Cdc4 was exclusively nuclear PMID:11080155 ubiquitylates Far1 in the nucleus, which in turn targets the multi-ubiquitylated PMID:11080155 Cdc4 is exclusively localized to the cell nucleus |
| GO:0050815 phosphoserine residue binding | IDA PMID:23314252 Sequential primed kinases create a damage-responsive phospho... | ACCEPT | Summary: Cdc4 binds the Eco1 diphosphodegron created by sequential Cdk1, Cdc7-Dbf4 and Mck1 phosphorylation; only the correctly spaced phospho-Thr94/phospho-Ser98 pair binds Cdc4, so phosphoserine recognition discriminates the kinases that licensed degradation. Reason: Core molecular function: phosphoresidue recognition by the WD40 propeller is the mechanism of the adaptor activity, and this paper maps it to a specific phosphoserine (Ser98) plus phosphothreonine (Thr94) pair on Eco1 with degron mutagenesis and binding assays. Complements GO:1990756 rather than duplicating it. Supporting Evidence: PMID:23314252 phosphorylation sites are spaced correctly to bind Cdc4, resulting in strict PMID:23314252 Phosphorylation of Thr94 and Ser98 promotes Cdc4 binding PMID:23314252 Cdc4 displays a preference for diphosphorylated degrons, often grouped in clusters |
| GO:0051321 meiotic cell cycle | IMP PMID:328339 Effects of the mitotic cell-cycle mutation cdc4 on yeast mei... | KEEP AS NON CORE | Summary: Temperature-shift experiments in cdc4/cdc4 diploids show that Cdc4 is required at several points in meiosis: arrest at the one-nucleus stage when shifted at the onset of sporulation, and additional arrest phenotypes after later shifts. Reason: Genuine requirement, but a 1977 phenotypic study that establishes necessity without a substrate; the later mechanistic literature (Cdc6 and Sic1 control in meiotic S phase and divisions) explains it through the same adaptor activity. Kept as a non-core organism-level process, consistent with grading substrate-specific downstream processes below the core SCF function. Supporting Evidence: PMID:328339 thus suggesting that the function of cdc4 is required at several points in meiosis (at least at three different times) PMID:328339 is arrested at the first division (one-nucleus stage) at the restrictive temperature |
| GO:0061630 ubiquitin protein ligase activity | IDA PMID:9346238 F-box proteins are receptors that recruit phosphorylated sub... | ACCEPT | Summary: As the substrate-recognition subunit of SCF(Cdc4), Cdc4 contributes to the ubiquitin ligase activity of the complex; the catalytic ubiquitin transfer is performed by Cdc34 docked on the Cdc53-Hrt1 core. Reason: Accepted on the contributes_to claim as seeded: E3 activity is a property of the assembled SCF(Cdc4) complex, and Cdc4 supplies the substrate-recognition arm without which the reconstituted complex has no substrate-directed activity. The molecular function of the subunit itself is best described as ubiquitin-like ligase-substrate adaptor activity (GO:1990756), which is proposed as the replacement for the bare protein-binding rows and used in core_functions. Skowyra et al. reconstituted the SCFCdc4 E3 with recombinant proteins and showed Cdc4-Skp1 is the receptor that selectively binds phosphorylated Sic1. Supporting Evidence: PMID:9346238 complex, SCFCdc4, which functions as a Sic1 ubiquitin-ligase (E3) in combination PMID:9346238 Skp1 functions as the receptor that selectively binds phosphorylated Sic1. file:yeast/CDC4/CDC4-deep-research-falcon.md Cdc4 is appropriately described as an **E3-complex substrate adaptor/receptor**, not as a catalytic ubiquitin-transfer enzyme in isolation. |
| GO:0061630 ubiquitin protein ligase activity | IMP PMID:21098119 SCFCdc4 enables mating type switching in yeast by cyclin-dep... | ACCEPT | Summary: As the substrate-recognition subunit of SCF(Cdc4), Cdc4 contributes to the ubiquitin ligase activity of the complex; the catalytic ubiquitin transfer is performed by Cdc34 docked on the Cdc53-Hrt1 core. Here SCF(Cdc4) eliminates the Ash1 transcriptional repressor after Cdc28 phosphorylation, enabling HO expression and mating-type switching in mother cells. Reason: Accepted on the contributes_to claim as seeded: E3 activity is a property of the assembled SCF(Cdc4) complex, and Cdc4 supplies the substrate-recognition arm without which the reconstituted complex has no substrate-directed activity. The molecular function of the subunit itself is best described as ubiquitin-like ligase-substrate adaptor activity (GO:1990756), which is proposed as the replacement for the bare protein-binding rows and used in core_functions. Inactivation of SCF(Cdc4) stabilises Ash1 in vivo, and Ash1 is bound and ubiquitinated by SCF(Cdc4) in vitro in a phosphorylation-dependent manner through two redundant diphosphorylated degrons; the abstract-only cache is sufficient to verify the claim. Supporting Evidence: PMID:21098119 mediates the phosphorylation-dependent elimination of Ash1 PMID:21098119 ubiquitinated by SCF(Cdc4) in a phosphorylation-dependent manner in vitro |
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Download this section (compressed HTML)Q: Which substrate underlies the Sic1-independent G2/M requirement for Cdc4 (cdc4 sic1-delta cells arrest before anaphase and the arrest is relieved by PDS1 deletion)? Is there a direct SCF(Cdc4) target among mitotic regulators, or is the effect indirect?
Q: Should the established phosphodegron substrates now recorded as bare protein binding on Cdc4 (Sic1, Rcn1) and the later ones absent from GOA (Far1, Cdc6, Gcn4, Swi5, Ash1, Eco1, Hst3, Tec1, Ame1) be modelled as has_input on the Cdc4 adaptor activity in a GO-CAM, rather than as GO:0005515 rows?
Q: Is Cdc4 homodimerisation through the D domain required for productive ubiquitination of all substrates, or only for those whose lysines lie far from the degron, and should a dimerisation activity be represented alongside the adaptor activity?
Experiment: Compare ubiquitin-remnant (diGly) proteomes of cdc4-12 sic1-delta and wild-type cells released from hydroxyurea at the restrictive temperature, filter candidates by Cdc4-phosphodegron motifs and Cdc4-WD40 binding, and test whether degron-mutant alleles of the top candidates reproduce the preanaphase arrest.
Hypothesis: The G2/M function of Cdc4 is mediated by a specific phosphodegron substrate whose stabilisation, not Pds1 turnover per se, causes the preanaphase arrest.
Type: conditional-allele ubiquitinome with degron mutagenesis
Experiment: Introduce the ubiquitin-binding-defective propeller mutations at the endogenous CDC4 locus and measure Sic1, Far1 and Cdc6 half-lives by cycloheximide chase and single-cell G1/S timing, with Cdc4 turnover measured in parallel.
Hypothesis: Ubiquitin binding by the Cdc4 WD40 propeller regulates only Cdc4 autoubiquitination and does not affect substrate ubiquitination kinetics in vivo.
Type: separation-of-function allele degradation kinetics
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