PTTG1 encodes securin, an intrinsically disordered cell-cycle regulator that binds the cysteine endopeptidase ESPL1/separase. Before anaphase, PTTG1 occupies the separase catalytic and substrate-docking surfaces and prevents premature cohesin cleavage; it also acts as an activating chaperone required for full separase competence. APC/C-dependent ubiquitination and proteasomal destruction of PTTG1 at the metaphase-to-anaphase transition release separase for chromosome segregation. PTTG1 functions in the separase-securin complex in nuclear and cytosolic pools, and balanced PTTG1 abundance is important for chromosome stability.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004869 cysteine-type endopeptidase inhibitor activity | IBA GO_REF:0000033 | ACCEPT | Summary: The phylogenetic inference captures the defining securin activity: PTTG1 binds the cysteine endopeptidase separase and inhibits access to its catalytic and substrate-docking sites. Reason: Human biochemical and cryo-EM studies directly establish inhibition of separase by PTTG1 pseudosubstrate motifs, so the transferred term is both specific and core. Supporting Evidence: PMID:34290405 Studies of truncated securin mutants revealed that this hydrophobic stretch is required for high-affinity securin-separase binding and inhibition of separase activity |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: Nuclear activity is consistent with PTTG1 control of chromosomal cohesin cleavage and with direct human subcellular-fractionation evidence. Reason: The reviewed human record and PMID:9811450 place PTTG1 in both the nucleus and cytoplasm; the nucleus is a biologically appropriate site of its chromosome-segregation function. Supporting Evidence: file:human/PTTG1/PTTG1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. Nucleus. |
| GO:0045143 homologous chromosome segregation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Conserved securin-separase regulation is relevant to meiotic chromosome segregation, and PTTG1 is strongly expressed in testis, but this is a meiosis-specific context rather than the primary mitotic role considered here. Reason: The IBA is biologically defensible across securin orthologs. Human-specific evidence in the cached set is indirect, so the term is retained as a contextual meiotic function rather than elevated to the core model. Supporting Evidence: PMID:9915854 results suggest that PTTG may play a role in spermatogenesis. |
| GO:0005634 nucleus | IEA GO_REF:0000120 | ACCEPT | Summary: The automated nuclear localization agrees with direct human fractionation and the reviewed UniProt subcellular-location statement. Reason: This is a correct cellular component and is independently represented by experimental and curated annotations in the same GOA set. Supporting Evidence: file:human/PTTG1/PTTG1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. Nucleus. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: The cytoplasmic prediction matches the original human fractionation study, which found PTTG1 to be predominantly cytosolic with a smaller nuclear pool. Reason: Cytoplasmic localization is directly supported and is compatible with separase sequestration and APC/C-dependent PTTG1 turnover. Supporting Evidence: PMID:9811450 although hPTTG is mainly a cytosolic protein |
| GO:0051276 chromosome organization | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO correctly detects chromosome-related biology but assigns a term much broader than PTTG1's established role in controlling the timing of sister-chromatid separation. Reason: The direct process is negative regulation of mitotic sister-chromatid separation through separase inhibition, not chromosome organization in general. Proposed replacements: negative regulation of mitotic sister chromatid separation Supporting Evidence: PMID:10411507 sister-chromatid separation but did not block the embryonic cell cycle. file:human/PTTG1/PTTG1-deep-research-manual.md PTTG1 prevents premature cohesin cleavage and thereby maintains sister-chromatid |
| GO:0005515 protein binding | IPI PMID:20360068 Systematic analysis of human protein complexes identifies ch... | MODIFY | Summary: The IntAct row identifies ESPL1/separase as the interaction partner in a systematic protein-complex study. Reason: Generic protein binding is uninformative. Because the named partner is the protease ESPL1, protease binding preserves the experimentally observed interaction at a useful level of specificity without assigning a regulatory consequence from this high-throughput experiment alone. Proposed replacements: protease binding Supporting Evidence: PMID:34290405 We determined the structures of a wild-type separase-securin complex |
| GO:0005515 protein binding | IPI PMID:24781523 PP2A delays APC/C-dependent degradation of separase-associat... | MODIFY | Summary: This targeted study analyzes separase-bound PTTG1 and its regulation by PP2A, directly supporting PTTG1 association with the separase protease. Reason: Protease binding is a more informative molecular-function term than generic protein binding and accurately describes the ESPL1 interaction. Proposed replacements: protease binding Supporting Evidence: PMID:24781523 Prior to anaphase onset, vertebrate separase is inhibited by mutually exclusive association with Cdk1-cyclin B1 or securin |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | MODIFY | Summary: The quantitative interactome row names ESPL1/separase as the PTTG1 interaction partner; the accessible article text describes the global AP-MS platform rather than this pair in detail. Reason: Protease binding is the appropriate informative refinement of this ESPL1-directed physical-interaction annotation. The known functional effects are supported by targeted studies and are curated separately. Proposed replacements: protease binding Supporting Evidence: PMID:34290405 We determined the structures of a wild-type separase-securin complex |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MODIFY | Summary: BioPlex reports the PTTG1-ESPL1 pair in a proteome-scale interaction map; the paper's accessible main text is platform-level rather than a focused validation of securin mechanism. Reason: The exact named partner is a protease, making protease binding a sound, more informative replacement. Targeted structural work independently confirms the same complex. Proposed replacements: protease binding Supporting Evidence: PMID:34290405 We determined the structures of a wild-type separase-securin complex |
| GO:0005515 protein binding | IPI PMID:34290405 Structural basis of human separase regulation by securin and... | MODIFY | Summary: Cryo-EM directly resolves PTTG1 bound along human ESPL1/separase and maps the inhibitory interfaces. Reason: The physical interaction is correct, but protease binding communicates the identity of the partner and is preferable to generic protein binding. Proposed replacements: protease binding Supporting Evidence: PMID:34290405 We determined the structures of a wild-type separase-securin complex |
| GO:0034088 maintenance of mitotic sister chromatid cohesion | NAS PMID:34290405 Structural basis of human separase regulation by securin and... | ACCEPT | Summary: PTTG1 maintains cohesion before anaphase by blocking ESPL1 access to cohesin substrates; PTTG1 destruction then permits cohesion dissolution. Reason: This process accurately captures the immediate mitotic consequence of the structurally demonstrated securin inhibition mechanism and is a core role. Supporting Evidence: PMID:12194817 the access of substrate analogs to the active site of separase. Reactome:R-HSA-2467798 PTTG1 sequesters ESPL1 and block its catalytic site, preventing it from cleaving centromeric cohesin and causing premature separation of sister chromatids |
| GO:0034090 maintenance of meiotic sister chromatid cohesion | NAS PMID:34290405 Structural basis of human separase regulation by securin and... | KEEP AS NON CORE | Summary: The conserved securin-separase switch also controls cohesin cleavage in meiosis, but the cited human structural paper does not directly test meiotic cells. Reason: Retain this plausible and curated meiotic role as context-specific. The cached evidence supports securin mechanism and testis expression but not a direct human meiotic perturbation, so it is not used as a core function. Supporting Evidence: PMID:9915854 results suggest that PTTG may play a role in spermatogenesis. |
| GO:1990520 separase-securin complex | IPI PMID:34290405 Structural basis of human separase regulation by securin and... | ACCEPT | Summary: PTTG1 is the securin subunit of the directly resolved human separase-securin complex. Reason: Direct cryo-EM structure and extensive biochemical interaction evidence establish core complex membership. Supporting Evidence: PMID:34290405 We determined the structures of a wild-type separase-securin complex |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence places PTTG1 in the cytosol, in agreement with direct biochemical fractionation and Reactome reactions. Reason: Cytosol is a directly supported PTTG1 compartment and is compatible with separase sequestration and APC/C-regulated turnover. Supporting Evidence: file:human/PTTG1/PTTG1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. Nucleus. |
| GO:0140677 molecular function activator activity | EXP PMID:15929994 Human full-length Securin is a natively unfolded protein. | MODIFY | Summary: PTTG1 has a separase-activating/chaperone function in addition to its inhibitory function, but the existing term is too generic and the cited biophysical paper is not the direct functional demonstration. Reason: Human genetic and domain-dissection studies identify ESPL1, a cysteine endopeptidase, as the activated enzyme. GO:0140608 states that specific activity, whereas PMID:15929994 chiefly establishes intrinsic disorder. Proposed replacements: cysteine-type endopeptidase activator activity Supporting Evidence: PMID:23798554 switched PTTG1 from an inhibitor into an activator of separase. PMID:11371342 mitoses were associated with biochemical defects in the activation of separin, |
| GO:0005634 nucleus | IDA PMID:9811450 hpttg, a human homologue of rat pttg, is overexpressed in he... | ACCEPT | Summary: Subcellular fractionation directly detected a nuclear PTTG1 pool. Reason: Direct human experimental evidence supports nuclear localization, which is also consistent with the site of chromosomal cohesin regulation. Supporting Evidence: file:human/PTTG1/PTTG1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. Nucleus. |
| GO:0005829 cytosol | IDA PMID:9811450 hpttg, a human homologue of rat pttg, is overexpressed in he... | ACCEPT | Summary: The same fractionation experiment found PTTG1 to be predominantly cytosolic. Reason: Direct human experimental evidence supports this compartment; it does not conflict with the smaller nuclear pool. Supporting Evidence: PMID:9811450 although hPTTG is mainly a cytosolic protein |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174088 | ACCEPT | Summary: Reactome places PTTG1 in a cytosolic APC/C:Cdh1 substrate-association reaction. Reason: The pathway compartment is consistent with direct human evidence for a major cytosolic PTTG1 pool. Supporting Evidence: file:human/PTTG1/PTTG1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. Nucleus. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174105 | ACCEPT | Summary: Reactome places APC/C-multiubiquitinated cell-cycle-protein degradation, including PTTG1 turnover, in the cytosol. Reason: Correct pathway compartment, independently compatible with the directly observed cytosolic PTTG1 pool. Supporting Evidence: file:human/PTTG1/PTTG1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. Nucleus. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174121 | ACCEPT | Summary: Reactome models cytosolic recognition of securin by the CDC20-APC/C complex through its destruction motifs. Reason: The modeled compartment agrees with direct fractionation and the known APC/C-dependent turnover mechanism. Supporting Evidence: file:human/PTTG1/PTTG1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. Nucleus. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174144 | ACCEPT | Summary: Reactome places APC/C:Cdc20-mediated PTTG1 ubiquitination in the cytosol. Reason: Correct pathway localization and consistent with the direct cytosolic localization evidence. Supporting Evidence: Reactome:R-HSA-174144 Securin is ubiquitinated by APC/C:Cdc20 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174195 | ACCEPT | Summary: The Reactome APC/C:Cdh1 ubiquitination reaction explicitly occurs in the cytosol. Reason: The pathway record explicitly supplies this compartment and agrees with the independently observed PTTG1 cytosolic pool. Supporting Evidence: Reactome:R-HSA-174195 This reaction takes place in the 'cytosol' |
| GO:0005829 cytosol | TAS Reactome:R-HSA-174202 | ACCEPT | Summary: Reactome places proteasomal degradation of multiubiquitinated securin in the cytosol. Reason: This compartment is consistent with both the pathway representation and direct PTTG1 localization data. Supporting Evidence: Reactome:R-HSA-174202 Following ubiquitination, securin is degraded by the 26S proteasome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2467798 | ACCEPT | Summary: Reactome models cytosolic sequestration of ESPL1 by PTTG1 before anaphase. Reason: The reaction directly represents the core separase-securin interaction in a compartment supported by human fractionation. Supporting Evidence: Reactome:R-HSA-2467798 Up to anaphase onset, ESPL1 (separase i.e. separin) forms a complex with PTTG1 |
| GO:0005634 nucleus | TAS PMID:9811450 hpttg, a human homologue of rat pttg, is overexpressed in he... | ACCEPT | Summary: The cited human fractionation study directly identifies a nuclear PTTG1 pool. Reason: Correct cellular component supported by the cited source and the reviewed UniProt record. Supporting Evidence: file:human/PTTG1/PTTG1-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm. Nucleus. |
| GO:0005737 cytoplasm | TAS PMID:9811450 hpttg, a human homologue of rat pttg, is overexpressed in he... | ACCEPT | Summary: The cited fractionation study found that most human PTTG1 was cytosolic. Reason: Direct human evidence supports the broader cytoplasm term; the annotation is compatible with the more specific cytosol rows. Supporting Evidence: PMID:9811450 although hPTTG is mainly a cytosolic protein |
| GO:0007283 spermatogenesis | TAS PMID:9915854 Pituitary tumor-transforming gene protein associates with ri... | KEEP AS NON CORE | Summary: PTTG expression is stage-specific in rat spermatocytes and spermatids, and the study identifies testicular interaction partners, but its functional conclusion is suggestive rather than a direct human perturbation. Reason: Retain the curated developmental context, supported by testis-enriched expression and conserved meiotic securin biology, while recognizing that it is secondary to the core cell-cycle function and not directly tested in human spermatogenesis in the accessible evidence. Supporting Evidence: PMID:9915854 results suggest that PTTG may play a role in spermatogenesis. |
| GO:0005515 protein binding | IPI PMID:12194817 Regulation of human separase by securin binding and autoclea... | MODIFY | Summary: Inhibitor-binding experiments directly show PTTG1/securin association with ESPL1/separase and occlusion of the protease active site. Reason: Protease binding is a more informative expression of the physical interaction than generic protein binding; the regulatory consequence is captured by the separate inhibitor annotation. Proposed replacements: protease binding Supporting Evidence: PMID:12194817 the access of substrate analogs to the active site of separase. |
| GO:0004869 cysteine-type endopeptidase inhibitor activity | NAS PMID:12194817 Regulation of human separase by securin binding and autoclea... | ACCEPT | Summary: The cited biochemical study directly demonstrates that securin inhibits separase by blocking substrate access to its active site. Reason: This is the central molecular activity of PTTG1 and is independently confirmed by the human separase-securin structure. Supporting Evidence: PMID:12194817 inhibits separase by blocking the access of substrates to the active site of PMID:34290405 Studies of truncated securin mutants revealed that this hydrophobic stretch is required for high-affinity securin-separase binding and inhibition of separase activity |
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Download this section (compressed HTML)Q: Which PTTG1 regions and conformational transitions promote separase folding or catalytic maturation independently of pseudosubstrate inhibition?
Q: Does PTTG1 have a direct, nonredundant role in human meiotic cohesion and spermatogenesis beyond its general separase-regulatory function?
Experiment: Reconstitute human ESPL1 synthesis or refolding with full-length PTTG1 and structure-guided PTTG1 fragments or interface mutants; measure ESPL1 stability, cohesin-substrate cleavage, inhibitor potency, and complex structure in parallel.
Hypothesis: PTTG1 contains a separase-activation module that is mechanistically separable from the H134-centered high-affinity inhibitory interface.
Type: Biochemical separation-of-function reconstitution
Experiment: Use inducible PTTG1 depletion in human germ-cell or gonadal-organoid models, with wild-type and activation- or inhibition-selective rescue alleles, and quantify meiotic cohesin cleavage, chromosome segregation, and aneuploidy by live imaging and single-cell karyotyping.
Hypothesis: PTTG1 directly protects meiotic cohesion in human germ-cell development.
Type: Human germ-cell perturbation and rescue
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The molecular basis and timing of PTTG1's separase-activating/chaperone function are less resolved than its pseudosubstrate-inhibitory mechanism.
OPEN BIOLOGY MF_DARK
What is known: Human knockout and domain-dissection experiments demonstrate an activation requirement, while the available human cryo-EM structure primarily explains inhibition.
Significance: Separating activation from inhibition is necessary to understand how PTTG1 abundance promotes or prevents chromosome instability.
What would resolve it: Reconstitute separase folding and catalytic maturation with defined PTTG1 fragments, then pair time-resolved activity measurements with structural analysis of activation-competent intermediates.
Provenance (the field's own admissions):
Gap: The direct requirement for PTTG1 in human spermatogenesis and meiotic cohesion has not been established by the locally accessible evidence.
OPEN BIOLOGY BP_DARK
What is known: The evidence set contains testis-enriched and stage-specific expression, interaction data, and conserved securin biology, but no direct perturbation of PTTG1 in human germ cells.
Significance: Resolving this would distinguish a direct germ-cell function from an expression-based extrapolation of the general securin mechanism.
What would resolve it: Perturb PTTG1 in human germ-cell or gonadal-organoid models and quantify meiotic cohesin cleavage, homolog segregation, aneuploidy, and rescue by inhibitor- versus activator-defective PTTG1 variants.
Provenance (the field's own admissions):
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