{"gene":"TTC5","run_date":"2026-04-28T21:43:00","timeline":{"discoveries":[{"year":2019,"finding":"TTC5 is a tubulin-specific ribosome-associating factor that binds near the ribosome exit tunnel and engages the amino terminus of nascent tubulins, triggering cotranslational degradation of tubulin mRNAs in response to excess soluble tubulin. TTC5 mutants incapable of ribosome or nascent tubulin interaction abolished tubulin autoregulation and showed chromosome segregation defects during mitosis.","method":"Structural analysis, in vitro biochemistry, mutagenesis, cell biology (chromosome segregation assay)","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — structure + mutagenesis + functional phenotype in single rigorous study","pmids":["31727855"],"is_preprint":false},{"year":2024,"finding":"Under normal conditions, soluble αβ-tubulins bind to and sequester TTC5, preventing it from engaging nascent tubulins at translating ribosomes. The flexible C-terminal tail of TTC5 acts as a molecular switch toggling between soluble αβ-tubulin-bound and nascent tubulin-bound states. Loss of sequestration constitutively activates TTC5, leading to diminished tubulin mRNA levels and compromised chromosome segregation.","method":"Biochemical and structural proteomic approaches, cryo-EM/structural proteomics, functional cell biology assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical reconstitution, structural proteomics, and functional validation in one study","pmids":["39551769"],"is_preprint":false},{"year":1998,"finding":"STRAP (TTC5) was identified as a WD40 domain-containing protein that interacts with both TGF-β type I (TβR-I) and type II (TβR-II) serine-threonine kinase receptors. Overexpression of STRAP inhibits TGF-β-mediated transcriptional activation and synergizes with Smad7 to inhibit TGF-β signaling.","method":"Yeast two-hybrid, co-immunoprecipitation, transcriptional reporter assays","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus functional reporter assays, foundational paper with >100 citations","pmids":["9856985"],"is_preprint":false},{"year":2000,"finding":"STRAP synergizes specifically with Smad7 (but not Smad6) to inhibit TGF-β signaling by recruiting Smad7 to the activated type I receptor, forming a ternary complex that stabilizes Smad7-receptor association and prevents Smad2/Smad3 access to the receptor. STRAP is phosphorylated in vivo in a TGF-β receptor kinase-dependent manner, requiring its C-terminus.","method":"Co-immunoprecipitation, transcriptional reporter assays, in vivo phosphorylation assay","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, replicated mechanistic findings, >100 citations","pmids":["10757800"],"is_preprint":false},{"year":2012,"finding":"Crystal structure of full-length STRAP (TTC5) at 2.05 Å resolution revealed an atypical six tetratricopeptide repeat (TPR) protein that also contains an unexpected oligonucleotide/oligosaccharide-binding (OB)-fold domain, providing an extended superhelical scaffold for protein-protein and protein-DNA interactions. Both TPR and OB-fold domains localize to chromatin of p53 target genes and exhibit intrinsic regulatory activity necessary for the Strap-dependent p53 response.","method":"X-ray crystallography, ChIP assay, functional mutagenesis","journal":"Proceedings of the National Academy of Sciences of the USA","confidence":"High","confidence_rationale":"Tier 1 — crystal structure at 2.05 Å with functional validation by ChIP","pmids":["22362889"],"is_preprint":false},{"year":2008,"finding":"ATM kinase phosphorylates STRAP (TTC5), facilitating its nuclear accumulation by impeding nuclear export, while Chk2 phosphorylation augments STRAP protein stability once it has attained a nuclear location, thereby coordinating p53 transcriptional responses to DNA damage.","method":"In vitro kinase assay, subcellular fractionation, protein stability assay, functional reporter assays","journal":"EMBO Reports","confidence":"High","confidence_rationale":"Tier 2 — direct kinase assay plus orthogonal functional assays","pmids":["18833288"],"is_preprint":false},{"year":2007,"finding":"STRAP (TTC5) interacts directly with the central DNA binding domain of p53 (residues 113-290) via Cys152 (or Cys270) of STRAP and Cys135 of p53, potentiating p53 transcriptional activity, apoptosis, and growth inhibition by removing Mdm2 from the p53-Mdm2 complex.","method":"Co-immunoprecipitation, mutagenesis, reporter assays, apoptosis assays","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with mutagenesis and multiple functional readouts","pmids":["17916563"],"is_preprint":false},{"year":2013,"finding":"STRAP (TTC5) is tethered to collagen α1(I) and α2(I) mRNAs via interaction with the RNA-binding protein LARP6, and interacts with eIF4A to restrain translation of collagen α2(I) mRNA. Absence of STRAP causes unrestricted loading of collagen α2(I) mRNA onto polysomes, imbalanced synthesis of collagen chains, hypermodification of α1(I), and failure of collagen trimer assembly.","method":"Co-immunoprecipitation, polysome profiling, pulldown, functional rescue experiments","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including polysome profiling and functional rescue","pmids":["23918805"],"is_preprint":false},{"year":2014,"finding":"STRAP (TTC5) is phosphorylated at Ser188 by MPK38 kinase via direct interaction mediated by Cys152/Cys270 of STRAP and Cys339/Cys377 of MPK38 (redox-dependent). This phosphorylation modulates STRAP's pro-apoptotic function through ASK1, TGF-β, p53, and PI3K/PDK1 signaling pathways.","method":"In vitro kinase assay, mutagenesis, Co-immunoprecipitation, inducible shRNA knockdown, adenoviral delivery in mice","journal":"Cell Cycle","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro kinase assay with mutagenesis and in vivo validation","pmids":["25485581"],"is_preprint":false},{"year":2014,"finding":"Mitochondrially-localized STRAP (TTC5) interacts with ATP synthase and downregulates mitochondrial ATP production. Under glucose-limiting conditions, mitochondrial STRAP sensitizes cancer cells to apoptosis, rescued by exogenous ATP. STRAP also augments the apoptotic effects of mitochondrial p53.","method":"Subcellular fractionation, co-immunoprecipitation, mitochondrial respiration assay, ATP measurement, apoptosis assay","journal":"Cell Death and Differentiation","confidence":"High","confidence_rationale":"Tier 2 — direct localization with functional consequence, Co-IP, multiple orthogonal methods","pmids":["25168243"],"is_preprint":false},{"year":2011,"finding":"STRAP binds GSK3β through its WD40 domains and forms a ternary complex with GSK3β and Axin. STRAP also binds the intracellular fragment of Notch3 (ICN3) through its ankyrin repeat region and reduces ubiquitination of ICN3, stabilizing it.","method":"Co-immunoprecipitation, in vivo ubiquitination assay, GSK3β inhibitor experiments","journal":"Cell Cycle","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with functional ubiquitination assay, single lab","pmids":["21502811"],"is_preprint":false},{"year":2016,"finding":"STRAP promotes β-catenin stability by binding GSK3β and reducing phosphorylation, ubiquitylation, and degradation of β-catenin through preventing its association with the destruction complex, thereby promoting Wnt/β-catenin signaling and CRC metastasis.","method":"Co-immunoprecipitation, ubiquitylation assay, in vitro and in vivo functional assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with functional validation, single lab","pmids":["26910283"],"is_preprint":false},{"year":2017,"finding":"STRAP competitively disrupts the association of PRC2 subunits EZH2 and SUZ12, thereby inhibiting PRC2 assembly, leading to reduced H3K27me3 at NOTCH pathway gene promoters and epigenetic activation of NOTCH signaling to maintain cancer stem cell subpopulations in colorectal cancer.","method":"Co-immunoprecipitation, ChIP assay, shRNA knockdown, tumorsphere assays, in vivo xenograft","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus ChIP with functional rescue experiments, single lab","pmids":["28827371"],"is_preprint":false},{"year":2020,"finding":"STRAP (TTC5) is a putative spliceosome-associated factor involved in the assembly of 17S U2 snRNP proteins. Upon Strap deletion in mouse embryoid bodies, numerous alternative splicing events occur, with STRAP preferentially targeting transcripts for nervous system development. In Xenopus, loss of Strap leads to impeded lineage differentiation, delayed neural tube closure, and altered exon skipping.","method":"eCLIP-seq, RNA-seq splicing analysis, deletion mouse model, Xenopus loss-of-function","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including eCLIP-seq and genetic epistasis across two model organisms","pmids":["33230114"],"is_preprint":false},{"year":2016,"finding":"STRAP acts as a scaffold protein in TLR2/4-mediated innate immune signaling by specifically binding TAK1 and IKKα along with NF-κB subunit p65, enhancing their association and facilitating p65 phosphorylation and nuclear translocation, resulting in enhanced pro-inflammatory cytokine production. At later times post-LPS stimulation, STRAP translocates to the nucleus and binds NF-κB to prolong IL-6 mRNA production.","method":"Co-immunoprecipitation, knockdown/overexpression, cytokine measurement, nuclear translocation assay","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with functional cytokine readouts, single lab","pmids":["27934954"],"is_preprint":false},{"year":2017,"finding":"STRAP acts as a positive scaffold regulator in TLR3-triggered signaling by strongly interacting with TBK1 and IRF3, enhancing IFN-β production. STRAP knockdown reduces pro-inflammatory cytokine and IFN levels, while overexpression increases them. The C-terminus of STRAP is essential for its functional activity.","method":"Co-immunoprecipitation, knockdown/overexpression, cytokine measurement","journal":"Cellular Immunology","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP with functional readouts, single lab","pmids":["28651742"],"is_preprint":false},{"year":2010,"finding":"B-MYB directly interacts with STRAP (TTC5) via its N-terminal DNA-binding domain and amino acids 373-468, positively regulating STRAP activity. B-MYB enhances STRAP-mediated inhibition of TGF-β signaling and STRAP-mediated p53-induced apoptosis by modulating complex formation between TGF-β receptor and SMAD3/SMAD7 and promoting p53 nuclear translocation.","method":"Co-immunoprecipitation, reporter assays, confocal microscopy, apoptosis assays","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct interaction mapping with functional consequence, single lab","pmids":["21148321"],"is_preprint":false},{"year":2020,"finding":"STRAP acetylation at lysines 147, 148, and 156 is mediated by the acetyltransferase CBP, and reversed by the deacetylase SIRT7. Hypo- or hyperacetylation mutations of STRAP at these sites influence p53 activation and stabilization. 5-FU treatment promotes STRAP mobilization from cytoplasm to nucleus and increases STRAP acetylation.","method":"In vitro acetylation assay, mutagenesis, subcellular fractionation, p53 activity assays","journal":"International Journal of Molecular Sciences","confidence":"Medium","confidence_rationale":"Tier 2 — identified writer/eraser with mutagenesis and functional validation, single lab","pmids":["32527012"],"is_preprint":false},{"year":2011,"finding":"STRAP regulates c-Jun stability by decreasing its ubiquitylation and proteasomal degradation; loss of STRAP accelerates c-Jun turnover and decreases cyclin D1 expression and cell growth without affecting JNK activity or c-Jun mRNA levels.","method":"Ubiquitylation assay, proteasome inhibitor experiments, mRNA and protein analysis, STRAP KO MEFs","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 — post-translational mechanism with KO model and ubiquitylation assay, single lab","pmids":["21397588"],"is_preprint":false},{"year":2014,"finding":"STRAP downregulates E-cadherin and p21(Cip1) by abrogating binding of transcription factor Sp1 to its consensus binding sites, and recruits HDAC1 to Sp1 binding sites in the p21(Cip1) promoter. Loss of STRAP stabilizes Sp1 by repressing its ubiquitination in G1 phase.","method":"ChIP assay, co-immunoprecipitation, ubiquitination assay, STRAP KO and KD cell models","journal":"Cell Cycle","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus ubiquitination assay, single lab","pmids":["25483064"],"is_preprint":false},{"year":2013,"finding":"TTC5 overexpression activates p53 pathway (up-regulating p53 and p21) and inhibits AP-1 transcriptional activity by significantly down-regulating expression, phosphorylation, and transcriptional activity of c-Jun, as well as expression and phosphorylation of the upstream kinase JNK/SAPK.","method":"Reporter assays, western blotting, overexpression experiments","journal":"Molecular Biology Reports","confidence":"Low","confidence_rationale":"Tier 3 — overexpression with reporter assays, no direct binding or mechanistic reconstitution, single lab","pmids":["24091941"],"is_preprint":false},{"year":2019,"finding":"TTC5/STRAP acts as a negative autophagy regulator by binding to JMY (junction mediating and regulatory protein), antagonizing JMY's actin nucleation activity and its LC3-mediated recruitment to phagophore membranes. In vitro reconstitution showed that membrane-bound LC3 is sufficient to recruit JMY and stimulate JMY-mediated actin filament assembly, which TTC5/STRAP antagonizes.","method":"In vitro reconstitution, Co-immunoprecipitation, actin polymerization assay","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro reconstitution described, multiple methods","pmids":["30593260"],"is_preprint":false},{"year":2018,"finding":"Csde1 (Cold shock domain protein e1/Unr) is the strongest Csde1-interacting protein in erythroblasts. Strap (TTC5) knockdown alters mRNA and/or protein expression of several Csde1-bound transcripts including Hmbs, eIF4g3, Pabpc4, Vim, and Elavl1, affecting translational regulation during hypoxia.","method":"Co-immunoprecipitation, RNA immunoprecipitation, shRNA knockdown, proteomics","journal":"PloS One","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and functional knockdown, single lab","pmids":["30138317"],"is_preprint":false},{"year":2025,"finding":"The Csde1-Strap complex binds Bach2 mRNA to couple its decay with translation, restraining the magnitude and duration of Bach2 protein expression to regulate plasma cell differentiation. Absence of Csde1 or Strap de-couples Bach2 translation from mRNA decay, leading to elevated and prolonged Bach2 protein and impaired plasma cell differentiation.","method":"RNA interactome capture, CRISPR functional screening, RIP, RNA-seq, protein stability assays","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including RIP and CRISPR screen with mechanistic rescue, strong evidence","pmids":["40133358"],"is_preprint":false},{"year":2008,"finding":"p49/STRAP (TTC5) interacts with NDUFAB1 (a subunit of NADH dehydrogenase), co-localizing in the cell, and overexpression of p49/STRAP alters intracellular NAD levels, reduces the NAD/NADH ratio, and induces deacetylation of serum response factor.","method":"Yeast two-hybrid, co-localization, NAD/NADH measurement, co-immunoprecipitation","journal":"BMC Cell Biology","confidence":"Low","confidence_rationale":"Tier 3 — yeast two-hybrid and single Co-IP with biochemical readout, single lab","pmids":["18230186"],"is_preprint":false},{"year":2009,"finding":"p49/STRAP (TTC5) interacts with the beta-sandwich domain of Hsp70, reduces Hsp40-stimulated ATPase activity of Hsp70, and inhibits the refolding activity of the Hsp70/Hsp40 chaperone system, qualifying it as a bona fide Hsp70 co-chaperone.","method":"Co-immunoprecipitation, ATPase assay, protein refolding assay","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro functional assays with domain identification, single lab","pmids":["19751705"],"is_preprint":false},{"year":2006,"finding":"p49/STRAP (TTC5) specifically interacts with the N-terminus of GLUT4 (acidic motif Q7IGSEDG), co-localizes with GLUT4 and ER-resident calnexin in adipose cells, and overexpression of the GLUT4-binding domain of p49 reduces protein synthesis and cell-surface expression of GLUT4.","method":"Yeast two-hybrid, confocal immunofluorescence co-localization, overexpression functional assay","journal":"Biochemical and Biophysical Research Communications","confidence":"Low","confidence_rationale":"Tier 3 — yeast two-hybrid and co-localization with functional consequence, single lab","pmids":["16647043"],"is_preprint":false},{"year":2025,"finding":"STRAP is S-nitrosylated by iNOS specifically at Cys152 and Cys270 (the same residues required for ASK1 interaction), which disrupts the STRAP-ASK1 interaction, increases ASK1 activity, activates MKK3-p38 pathway, and enhances hydrogen peroxide-induced apoptosis. STRAP-C152/270S mutation constitutively activates the ASK1-MKK3-p38 pathway.","method":"S-nitrosylation assay, mutagenesis, Co-immunoprecipitation, kinase activity assay, apoptosis assay","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — novel PTM identified with mutagenesis, biochemical reconstitution, and clear mechanistic pathway","pmids":["41519199"],"is_preprint":false},{"year":2025,"finding":"USP38 stabilizes STRAP via deubiquitination, thereby enhancing TGF-β/SMAD signaling and promoting atrial fibrosis in CKD-associated atrial fibrillation. STRAP knockdown reversed the pro-fibrotic effects induced by USP38 overexpression.","method":"Co-immunoprecipitation, ubiquitination assay, KO and TG mouse models, immunofluorescence","journal":"Molecular Medicine","confidence":"Medium","confidence_rationale":"Tier 2 — identified deubiquitinase with functional genetic validation in mouse models","pmids":["40514673"],"is_preprint":false},{"year":2025,"finding":"In C. elegans neurons, TTC5 (ttc-5) is required to recruit γ-tubulin to endosomal puncta (non-centrosomal MTOCs) for microtubule nucleation. Loss of ttc-5 reduces MT numbers similarly to γ-tubulin depletion and is essential for axon regeneration, where TTC5 directs γ-tubulin to the growth cone.","method":"C. elegans genetics, conditional single-cell degradation alleles, endogenous tagging, live imaging, axon regeneration assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by live imaging with functional consequence in genetic model, preprint","pmids":["41279556"],"is_preprint":true},{"year":2025,"finding":"Loss of TTC5-dependent tubulin autoregulation elevates soluble tubulin levels and induces microtubule hyperstability, disrupting cytoskeletal organization. This impairs localization of adhesion molecules at cell-cell junctions and extracellular matrix interfaces, compromising tissue architecture and reducing cell viability in human 3D cellular models.","method":"Human 3D cellular models, advanced optics, genetic perturbation, functional tissue assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — genetic perturbation with specific cellular phenotype and mechanistic pathway, preprint","pmids":["bio_10.1101_2025.07.28.667019"],"is_preprint":true},{"year":2024,"finding":"circPCNXL2 directly binds to STRAP and induces the interaction between STRAP and MEK1/2, resulting in activation of ERK/MAPK pathway and promoting ICC tumor growth and metastasis.","method":"RNA pulldown, mass spectrometry, RIP, Co-immunoprecipitation, functional cell and in vivo assays","journal":"Molecular Cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 — RNA pulldown with MS and functional validation, single lab","pmids":["38365721"],"is_preprint":false}],"current_model":"TTC5 (STRAP) is a tetratricopeptide repeat/OB-fold scaffold protein with dual molecular functions: (1) as a tubulin-specific cotranslational quality control factor that binds near the ribosome exit tunnel to recognize nascent tubulin N-termini and trigger mRNA deadenylation/degradation in response to excess soluble αβ-tubulins (which normally sequester TTC5 via its flexible C-terminal tail to keep it inactive), and (2) as a multifunctional scaffold in numerous signaling pathways including TGF-β/Smad, p53/p300, Wnt/β-catenin, NF-κB/TLR, and mRNA translation/splicing regulation, operating through direct protein-protein interactions with TβR-I/II, Smad7, p53, GSK3β, ATP synthase, eIF4A, U2 snRNP components, and the Csde1 RNA-binding complex."},"narrative":{"teleology":[{"year":1998,"claim":"Identification of TTC5 (STRAP) as a TGF-β receptor-interacting protein established it as a negative regulator of TGF-β signaling, opening investigation into its scaffold function.","evidence":"Yeast two-hybrid screen and co-immunoprecipitation with TβR-I/II plus transcriptional reporter assays in mammalian cells","pmids":["9856985"],"confidence":"High","gaps":["Mechanism of inhibition at the receptor level was not defined","No structural data on how STRAP contacts the receptors"]},{"year":2000,"claim":"The mechanism of TGF-β inhibition was resolved: STRAP recruits Smad7 specifically to the activated type I receptor, forming a ternary complex that blocks Smad2/3 access, and STRAP itself is phosphorylated in a receptor kinase-dependent manner.","evidence":"Co-immunoprecipitation showing ternary complex, reporter assays, in vivo phosphorylation analysis","pmids":["10757800"],"confidence":"High","gaps":["Identity of the specific phosphorylated residue on STRAP was not mapped","In vivo relevance in animal models was not tested"]},{"year":2007,"claim":"Discovery that TTC5 directly binds p53's DNA-binding domain and displaces Mdm2 established a second major signaling axis — p53 activation — mechanistically distinct from TGF-β inhibition.","evidence":"Reciprocal co-immunoprecipitation, cysteine mutagenesis (Cys152/Cys270 on STRAP, Cys135 on p53), reporter and apoptosis assays","pmids":["17916563"],"confidence":"High","gaps":["No structural basis for STRAP-p53 interaction","Relevance in DNA damage context not yet tested"]},{"year":2008,"claim":"The DNA damage-responsive regulation of TTC5 was established: ATM phosphorylation drives nuclear accumulation by blocking export, while Chk2 phosphorylation stabilizes nuclear TTC5, explaining how p53 coactivation is triggered by genotoxic stress.","evidence":"In vitro kinase assays, subcellular fractionation, protein stability assays","pmids":["18833288"],"confidence":"High","gaps":["Exact phosphorylation sites on STRAP were not all mapped","Genetic epistasis in vivo was not performed"]},{"year":2011,"claim":"Binding of TTC5 to GSK3β and Axin, and stabilization of Notch3 intracellular domain via reduced ubiquitination, linked TTC5 to Wnt and Notch signaling pathways beyond TGF-β and p53.","evidence":"Co-immunoprecipitation and in vivo ubiquitination assays with GSK3β inhibitor controls","pmids":["21502811"],"confidence":"Medium","gaps":["Structural basis for GSK3β interaction not determined","Wnt pathway functional consequences not shown in this study","Single-lab finding"]},{"year":2012,"claim":"The crystal structure of full-length TTC5 at 2.05 Å revealed an atypical six-TPR plus OB-fold architecture, explaining its capacity for diverse protein–protein and protein–DNA interactions, and both domains were shown to localize to chromatin of p53 target genes.","evidence":"X-ray crystallography, ChIP assays, functional mutagenesis","pmids":["22362889"],"confidence":"High","gaps":["No co-crystal structures with any binding partner","How each domain individually contributes to different signaling axes was not dissected"]},{"year":2013,"claim":"TTC5 was shown to regulate collagen biosynthesis by tethering to collagen mRNAs via LARP6 and restraining translation of collagen α2(I) mRNA through interaction with eIF4A, revealing a translational regulatory function.","evidence":"Co-immunoprecipitation, polysome profiling, pulldown, functional rescue in STRAP-deficient cells","pmids":["23918805"],"confidence":"High","gaps":["Whether TTC5 directly contacts mRNA or only acts through LARP6 was not resolved","Structural basis of eIF4A interaction unknown"]},{"year":2016,"claim":"TTC5 was established as a scaffold in innate immune signaling: it bridges TAK1, IKKα, and NF-κB p65 to facilitate p65 phosphorylation and nuclear translocation in TLR2/4 pathways, with subsequent nuclear TTC5 prolonging cytokine transcription.","evidence":"Co-immunoprecipitation, knockdown/overexpression with cytokine measurement, nuclear translocation assay","pmids":["27934954"],"confidence":"Medium","gaps":["Single-lab study","No structural basis for multi-protein scaffold assembly","Relative contribution vs. other NF-κB scaffolds not assessed"]},{"year":2016,"claim":"Functional demonstration that TTC5 promotes Wnt/β-catenin signaling by binding GSK3β and preventing β-catenin phosphorylation and degradation, with consequences for CRC metastasis, extended the GSK3β interaction to a defined oncogenic pathway.","evidence":"Co-immunoprecipitation, ubiquitylation assay, in vitro and in vivo metastasis assays","pmids":["26910283"],"confidence":"Medium","gaps":["Single-lab study","Whether TTC5 competes with Axin for GSK3β binding was not tested"]},{"year":2019,"claim":"A paradigm shift: TTC5 was identified as a tubulin-specific ribosome-associated quality control factor that binds near the exit tunnel, recognizes nascent tubulin N-termini, and triggers cotranslational mRNA degradation, with loss-of-function causing chromosome segregation defects.","evidence":"Structural analysis, in vitro biochemistry, mutagenesis ablating ribosome and nascent-chain interactions, mitotic phenotyping","pmids":["31727855"],"confidence":"High","gaps":["Mechanism linking TTC5-nascent tubulin recognition to mRNA deadenylation machinery not defined","Whether other nascent chains besides tubulins are recognized was not tested"]},{"year":2019,"claim":"TTC5 was shown to negatively regulate autophagy by binding JMY and antagonizing its LC3-dependent recruitment to phagophore membranes and actin nucleation activity.","evidence":"In vitro reconstitution with membrane-bound LC3, co-immunoprecipitation, actin polymerization assay","pmids":["30593260"],"confidence":"Medium","gaps":["In vivo relevance to autophagic flux not demonstrated in animal models","Whether TTC5-JMY interaction is regulated by tubulin levels is unknown"]},{"year":2020,"claim":"TTC5 was established as a spliceosome-associated factor involved in 17S U2 snRNP assembly; its deletion caused widespread alternative splicing changes preferentially targeting nervous system transcripts, and loss in Xenopus impaired neural tube closure.","evidence":"eCLIP-seq, RNA-seq splicing analysis, mouse embryoid body deletion model, Xenopus loss-of-function","pmids":["33230114"],"confidence":"High","gaps":["Direct RNA-binding specificity of TTC5 versus indirect recruitment via U2 snRNP not resolved","Whether the splicing function is independent of the tubulin autoregulation role is unclear"]},{"year":2024,"claim":"The autoregulatory switch mechanism was resolved: soluble αβ-tubulins sequester TTC5 via its flexible C-terminal tail under normal conditions, preventing constitutive engagement of nascent tubulins at ribosomes; loss of this sequestration constitutively activates TTC5 and depletes tubulin mRNAs.","evidence":"Cryo-EM/structural proteomics, biochemical reconstitution, functional cell biology assays","pmids":["39551769"],"confidence":"High","gaps":["Identity of the deadenylase/decay machinery recruited by active TTC5 remains unknown","Whether other factors modulate the C-terminal tail switch is untested"]},{"year":2025,"claim":"The Csde1–TTC5 complex was shown to couple Bach2 mRNA decay with translation during plasma cell differentiation, establishing TTC5 as a component of a post-transcriptional regulatory module controlling immune cell fate decisions.","evidence":"RNA interactome capture, CRISPR functional screen, RIP, RNA-seq, protein stability assays in B cells","pmids":["40133358"],"confidence":"High","gaps":["Whether TTC5 contributes RNA-binding activity or acts solely as a scaffold within the Csde1 complex is not resolved","Generality to other Csde1-regulated transcripts beyond Bach2 not tested systematically"]},{"year":2025,"claim":"S-nitrosylation of TTC5 at Cys152 and Cys270 by iNOS was identified as a regulatory switch that disrupts TTC5-ASK1 interaction, activating the ASK1-MKK3-p38 apoptotic pathway, revealing redox-dependent control of TTC5 scaffold function.","evidence":"S-nitrosylation assay, cysteine mutagenesis, co-immunoprecipitation, kinase activity assay, apoptosis assay","pmids":["41519199"],"confidence":"High","gaps":["Physiological contexts in which iNOS-mediated S-nitrosylation of TTC5 is triggered are not defined","Interplay between S-nitrosylation and other PTMs at the same cysteines is unknown"]},{"year":null,"claim":"Key unresolved questions include: the identity of the mRNA decay machinery recruited by TTC5 during tubulin autoregulation; whether the tubulin quality control and signaling scaffold functions operate through the same structural surfaces or are mutually exclusive; and whether TTC5's splicing role is mechanistically linked to its translational regulatory activities.","evidence":"","pmids":[],"confidence":"Low","gaps":["No reconstitution of the complete tubulin autoregulation pathway from TTC5 to deadenylation/decay factors","Structural basis for simultaneous engagement of multiple partners is unknown","Functional hierarchy among TTC5's diverse roles in vivo has not been established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,3,10,11,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,7,21,25]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[13,22,23]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,17]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4,5,14,17]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[9]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,10,11,14,15,31]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6,8,9,27]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,13,23]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,15]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7,25]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[21]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,6]}],"complexes":["Csde1-Strap complex","17S U2 snRNP"],"partners":["TGFBR1","SMAD7","TP53","GSK3B","CSDE1","JMY","LARP6","MAP3K5"],"other_free_text":[]},"mechanistic_narrative":"TTC5 (also known as STRAP) is a TPR/OB-fold scaffold protein that functions as a tubulin-specific cotranslational quality control factor and as a multivalent signaling adaptor across several major cellular pathways. In its tubulin autoregulatory role, TTC5 binds near the ribosome exit tunnel to recognize nascent tubulin N-termini and triggers tubulin mRNA degradation when soluble αβ-tubulin levels are elevated; under basal conditions, soluble tubulins sequester TTC5 via its flexible C-terminal tail, keeping this activity suppressed, and loss of this autoregulation causes chromosome segregation defects [PMID:31727855, PMID:39551769]. As a signaling scaffold, TTC5 inhibits TGF-β signaling by recruiting Smad7 to activated type I receptors [PMID:9856985, PMID:10757800], potentiates p53 transcriptional activity by displacing Mdm2 and localizing to chromatin of p53 target genes under DNA damage-induced ATM/Chk2 phosphorylation [PMID:17916563, PMID:18833288, PMID:22362889], promotes Wnt/β-catenin signaling by binding GSK3β to protect β-catenin from destruction complex-mediated degradation [PMID:26910283], and participates in U2 snRNP assembly to regulate alternative splicing of transcripts critical for nervous system development [PMID:33230114]. TTC5 also forms a complex with Csde1 to couple mRNA decay with translation, as demonstrated for Bach2 mRNA during plasma cell differentiation [PMID:40133358], and negatively regulates autophagy by antagonizing JMY-mediated actin nucleation at phagophore membranes [PMID:30593260]."},"prefetch_data":{"uniprot":{"accession":"Q8N0Z6","full_name":"Tetratricopeptide repeat protein 5","aliases":["Stress-responsive activator of p300","Protein Strap"],"length_aa":440,"mass_kda":48.9,"function":"Cofactor involved in the regulation of various cellular mechanisms such as actin regulation, autophagy, chromatin regulation and DNA repair (PubMed:18451878, PubMed:31727855). In non-stress conditions, interacts with cofactor JMY in the cytoplasm which prevents JMY's actin nucleation activity and ability to activate the Arp2/3 complex. Acts as a negative regulator of nutrient stress-induced autophagy by preventing JMY's interaction with MAP1LC3B, thereby preventing autophagosome formation (By similarity). Involves in tubulin autoregulation by promoting its degradation in response to excess soluble tubulin (PubMed:31727855). To do so, associates with the active ribosome near the ribosome exit tunnel and with nascent tubulin polypeptides early during their translation, triggering tubulin mRNA-targeted degradation (PubMed:31727855). Following DNA damage, phosphorylated by DNA damage responsive protein kinases ATM and CHEK2, leading to its nuclear accumulation and stability. Nuclear TTC5/STRAP promotes the assembly of a stress-responsive p53/TP53 coactivator complex, which includes the coactivators JMY and p300, thereby increasing p53/TP53-dependent transcription and apoptosis. Also recruits arginine methyltransferase PRMT5 to p53/TP53 when DNA is damaged, allowing PRMT5 to methylate p53/TP53. In DNA stress conditions, also prevents p53/TP53 degradation by E3 ubiquitin ligase MDM2 (By similarity). Upon heat-shock stress, forms a chromatin-associated complex with heat-shock factor 1 HSF1 and p300/EP300 to stimulate heat-shock-responsive transcription, thereby increasing cell survival (PubMed:18451878). Mitochondrial TTC5/STRAP interacts with ATP synthase subunit beta ATP5F1B which decreased ATP synthase activity and lowers mitochondrial ATP production, thereby regulating cellular respiration and mitochondrial-dependent apoptosis. 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TTC5 mutants incapable of ribosome or nascent tubulin interaction abolished tubulin autoregulation and showed chromosome segregation defects during mitosis.\",\n      \"method\": \"Structural analysis, in vitro biochemistry, mutagenesis, cell biology (chromosome segregation assay)\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure + mutagenesis + functional phenotype in single rigorous study\",\n      \"pmids\": [\"31727855\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Under normal conditions, soluble αβ-tubulins bind to and sequester TTC5, preventing it from engaging nascent tubulins at translating ribosomes. The flexible C-terminal tail of TTC5 acts as a molecular switch toggling between soluble αβ-tubulin-bound and nascent tubulin-bound states. Loss of sequestration constitutively activates TTC5, leading to diminished tubulin mRNA levels and compromised chromosome segregation.\",\n      \"method\": \"Biochemical and structural proteomic approaches, cryo-EM/structural proteomics, functional cell biology assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical reconstitution, structural proteomics, and functional validation in one study\",\n      \"pmids\": [\"39551769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"STRAP (TTC5) was identified as a WD40 domain-containing protein that interacts with both TGF-β type I (TβR-I) and type II (TβR-II) serine-threonine kinase receptors. Overexpression of STRAP inhibits TGF-β-mediated transcriptional activation and synergizes with Smad7 to inhibit TGF-β signaling.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, transcriptional reporter assays\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional reporter assays, foundational paper with >100 citations\",\n      \"pmids\": [\"9856985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"STRAP synergizes specifically with Smad7 (but not Smad6) to inhibit TGF-β signaling by recruiting Smad7 to the activated type I receptor, forming a ternary complex that stabilizes Smad7-receptor association and prevents Smad2/Smad3 access to the receptor. STRAP is phosphorylated in vivo in a TGF-β receptor kinase-dependent manner, requiring its C-terminus.\",\n      \"method\": \"Co-immunoprecipitation, transcriptional reporter assays, in vivo phosphorylation assay\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, replicated mechanistic findings, >100 citations\",\n      \"pmids\": [\"10757800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structure of full-length STRAP (TTC5) at 2.05 Å resolution revealed an atypical six tetratricopeptide repeat (TPR) protein that also contains an unexpected oligonucleotide/oligosaccharide-binding (OB)-fold domain, providing an extended superhelical scaffold for protein-protein and protein-DNA interactions. Both TPR and OB-fold domains localize to chromatin of p53 target genes and exhibit intrinsic regulatory activity necessary for the Strap-dependent p53 response.\",\n      \"method\": \"X-ray crystallography, ChIP assay, functional mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the USA\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure at 2.05 Å with functional validation by ChIP\",\n      \"pmids\": [\"22362889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ATM kinase phosphorylates STRAP (TTC5), facilitating its nuclear accumulation by impeding nuclear export, while Chk2 phosphorylation augments STRAP protein stability once it has attained a nuclear location, thereby coordinating p53 transcriptional responses to DNA damage.\",\n      \"method\": \"In vitro kinase assay, subcellular fractionation, protein stability assay, functional reporter assays\",\n      \"journal\": \"EMBO Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct kinase assay plus orthogonal functional assays\",\n      \"pmids\": [\"18833288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"STRAP (TTC5) interacts directly with the central DNA binding domain of p53 (residues 113-290) via Cys152 (or Cys270) of STRAP and Cys135 of p53, potentiating p53 transcriptional activity, apoptosis, and growth inhibition by removing Mdm2 from the p53-Mdm2 complex.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis, reporter assays, apoptosis assays\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with mutagenesis and multiple functional readouts\",\n      \"pmids\": [\"17916563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"STRAP (TTC5) is tethered to collagen α1(I) and α2(I) mRNAs via interaction with the RNA-binding protein LARP6, and interacts with eIF4A to restrain translation of collagen α2(I) mRNA. Absence of STRAP causes unrestricted loading of collagen α2(I) mRNA onto polysomes, imbalanced synthesis of collagen chains, hypermodification of α1(I), and failure of collagen trimer assembly.\",\n      \"method\": \"Co-immunoprecipitation, polysome profiling, pulldown, functional rescue experiments\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including polysome profiling and functional rescue\",\n      \"pmids\": [\"23918805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"STRAP (TTC5) is phosphorylated at Ser188 by MPK38 kinase via direct interaction mediated by Cys152/Cys270 of STRAP and Cys339/Cys377 of MPK38 (redox-dependent). This phosphorylation modulates STRAP's pro-apoptotic function through ASK1, TGF-β, p53, and PI3K/PDK1 signaling pathways.\",\n      \"method\": \"In vitro kinase assay, mutagenesis, Co-immunoprecipitation, inducible shRNA knockdown, adenoviral delivery in mice\",\n      \"journal\": \"Cell Cycle\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase assay with mutagenesis and in vivo validation\",\n      \"pmids\": [\"25485581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Mitochondrially-localized STRAP (TTC5) interacts with ATP synthase and downregulates mitochondrial ATP production. Under glucose-limiting conditions, mitochondrial STRAP sensitizes cancer cells to apoptosis, rescued by exogenous ATP. STRAP also augments the apoptotic effects of mitochondrial p53.\",\n      \"method\": \"Subcellular fractionation, co-immunoprecipitation, mitochondrial respiration assay, ATP measurement, apoptosis assay\",\n      \"journal\": \"Cell Death and Differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional consequence, Co-IP, multiple orthogonal methods\",\n      \"pmids\": [\"25168243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"STRAP binds GSK3β through its WD40 domains and forms a ternary complex with GSK3β and Axin. STRAP also binds the intracellular fragment of Notch3 (ICN3) through its ankyrin repeat region and reduces ubiquitination of ICN3, stabilizing it.\",\n      \"method\": \"Co-immunoprecipitation, in vivo ubiquitination assay, GSK3β inhibitor experiments\",\n      \"journal\": \"Cell Cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with functional ubiquitination assay, single lab\",\n      \"pmids\": [\"21502811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"STRAP promotes β-catenin stability by binding GSK3β and reducing phosphorylation, ubiquitylation, and degradation of β-catenin through preventing its association with the destruction complex, thereby promoting Wnt/β-catenin signaling and CRC metastasis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assay, in vitro and in vivo functional assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with functional validation, single lab\",\n      \"pmids\": [\"26910283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STRAP competitively disrupts the association of PRC2 subunits EZH2 and SUZ12, thereby inhibiting PRC2 assembly, leading to reduced H3K27me3 at NOTCH pathway gene promoters and epigenetic activation of NOTCH signaling to maintain cancer stem cell subpopulations in colorectal cancer.\",\n      \"method\": \"Co-immunoprecipitation, ChIP assay, shRNA knockdown, tumorsphere assays, in vivo xenograft\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus ChIP with functional rescue experiments, single lab\",\n      \"pmids\": [\"28827371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"STRAP (TTC5) is a putative spliceosome-associated factor involved in the assembly of 17S U2 snRNP proteins. Upon Strap deletion in mouse embryoid bodies, numerous alternative splicing events occur, with STRAP preferentially targeting transcripts for nervous system development. In Xenopus, loss of Strap leads to impeded lineage differentiation, delayed neural tube closure, and altered exon skipping.\",\n      \"method\": \"eCLIP-seq, RNA-seq splicing analysis, deletion mouse model, Xenopus loss-of-function\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including eCLIP-seq and genetic epistasis across two model organisms\",\n      \"pmids\": [\"33230114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"STRAP acts as a scaffold protein in TLR2/4-mediated innate immune signaling by specifically binding TAK1 and IKKα along with NF-κB subunit p65, enhancing their association and facilitating p65 phosphorylation and nuclear translocation, resulting in enhanced pro-inflammatory cytokine production. At later times post-LPS stimulation, STRAP translocates to the nucleus and binds NF-κB to prolong IL-6 mRNA production.\",\n      \"method\": \"Co-immunoprecipitation, knockdown/overexpression, cytokine measurement, nuclear translocation assay\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with functional cytokine readouts, single lab\",\n      \"pmids\": [\"27934954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STRAP acts as a positive scaffold regulator in TLR3-triggered signaling by strongly interacting with TBK1 and IRF3, enhancing IFN-β production. STRAP knockdown reduces pro-inflammatory cytokine and IFN levels, while overexpression increases them. The C-terminus of STRAP is essential for its functional activity.\",\n      \"method\": \"Co-immunoprecipitation, knockdown/overexpression, cytokine measurement\",\n      \"journal\": \"Cellular Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP with functional readouts, single lab\",\n      \"pmids\": [\"28651742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"B-MYB directly interacts with STRAP (TTC5) via its N-terminal DNA-binding domain and amino acids 373-468, positively regulating STRAP activity. B-MYB enhances STRAP-mediated inhibition of TGF-β signaling and STRAP-mediated p53-induced apoptosis by modulating complex formation between TGF-β receptor and SMAD3/SMAD7 and promoting p53 nuclear translocation.\",\n      \"method\": \"Co-immunoprecipitation, reporter assays, confocal microscopy, apoptosis assays\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct interaction mapping with functional consequence, single lab\",\n      \"pmids\": [\"21148321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"STRAP acetylation at lysines 147, 148, and 156 is mediated by the acetyltransferase CBP, and reversed by the deacetylase SIRT7. Hypo- or hyperacetylation mutations of STRAP at these sites influence p53 activation and stabilization. 5-FU treatment promotes STRAP mobilization from cytoplasm to nucleus and increases STRAP acetylation.\",\n      \"method\": \"In vitro acetylation assay, mutagenesis, subcellular fractionation, p53 activity assays\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — identified writer/eraser with mutagenesis and functional validation, single lab\",\n      \"pmids\": [\"32527012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"STRAP regulates c-Jun stability by decreasing its ubiquitylation and proteasomal degradation; loss of STRAP accelerates c-Jun turnover and decreases cyclin D1 expression and cell growth without affecting JNK activity or c-Jun mRNA levels.\",\n      \"method\": \"Ubiquitylation assay, proteasome inhibitor experiments, mRNA and protein analysis, STRAP KO MEFs\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — post-translational mechanism with KO model and ubiquitylation assay, single lab\",\n      \"pmids\": [\"21397588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"STRAP downregulates E-cadherin and p21(Cip1) by abrogating binding of transcription factor Sp1 to its consensus binding sites, and recruits HDAC1 to Sp1 binding sites in the p21(Cip1) promoter. Loss of STRAP stabilizes Sp1 by repressing its ubiquitination in G1 phase.\",\n      \"method\": \"ChIP assay, co-immunoprecipitation, ubiquitination assay, STRAP KO and KD cell models\",\n      \"journal\": \"Cell Cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus ubiquitination assay, single lab\",\n      \"pmids\": [\"25483064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TTC5 overexpression activates p53 pathway (up-regulating p53 and p21) and inhibits AP-1 transcriptional activity by significantly down-regulating expression, phosphorylation, and transcriptional activity of c-Jun, as well as expression and phosphorylation of the upstream kinase JNK/SAPK.\",\n      \"method\": \"Reporter assays, western blotting, overexpression experiments\",\n      \"journal\": \"Molecular Biology Reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — overexpression with reporter assays, no direct binding or mechanistic reconstitution, single lab\",\n      \"pmids\": [\"24091941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TTC5/STRAP acts as a negative autophagy regulator by binding to JMY (junction mediating and regulatory protein), antagonizing JMY's actin nucleation activity and its LC3-mediated recruitment to phagophore membranes. In vitro reconstitution showed that membrane-bound LC3 is sufficient to recruit JMY and stimulate JMY-mediated actin filament assembly, which TTC5/STRAP antagonizes.\",\n      \"method\": \"In vitro reconstitution, Co-immunoprecipitation, actin polymerization assay\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution described, multiple methods\",\n      \"pmids\": [\"30593260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Csde1 (Cold shock domain protein e1/Unr) is the strongest Csde1-interacting protein in erythroblasts. Strap (TTC5) knockdown alters mRNA and/or protein expression of several Csde1-bound transcripts including Hmbs, eIF4g3, Pabpc4, Vim, and Elavl1, affecting translational regulation during hypoxia.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation, shRNA knockdown, proteomics\",\n      \"journal\": \"PloS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and functional knockdown, single lab\",\n      \"pmids\": [\"30138317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The Csde1-Strap complex binds Bach2 mRNA to couple its decay with translation, restraining the magnitude and duration of Bach2 protein expression to regulate plasma cell differentiation. Absence of Csde1 or Strap de-couples Bach2 translation from mRNA decay, leading to elevated and prolonged Bach2 protein and impaired plasma cell differentiation.\",\n      \"method\": \"RNA interactome capture, CRISPR functional screening, RIP, RNA-seq, protein stability assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including RIP and CRISPR screen with mechanistic rescue, strong evidence\",\n      \"pmids\": [\"40133358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"p49/STRAP (TTC5) interacts with NDUFAB1 (a subunit of NADH dehydrogenase), co-localizing in the cell, and overexpression of p49/STRAP alters intracellular NAD levels, reduces the NAD/NADH ratio, and induces deacetylation of serum response factor.\",\n      \"method\": \"Yeast two-hybrid, co-localization, NAD/NADH measurement, co-immunoprecipitation\",\n      \"journal\": \"BMC Cell Biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid and single Co-IP with biochemical readout, single lab\",\n      \"pmids\": [\"18230186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"p49/STRAP (TTC5) interacts with the beta-sandwich domain of Hsp70, reduces Hsp40-stimulated ATPase activity of Hsp70, and inhibits the refolding activity of the Hsp70/Hsp40 chaperone system, qualifying it as a bona fide Hsp70 co-chaperone.\",\n      \"method\": \"Co-immunoprecipitation, ATPase assay, protein refolding assay\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro functional assays with domain identification, single lab\",\n      \"pmids\": [\"19751705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"p49/STRAP (TTC5) specifically interacts with the N-terminus of GLUT4 (acidic motif Q7IGSEDG), co-localizes with GLUT4 and ER-resident calnexin in adipose cells, and overexpression of the GLUT4-binding domain of p49 reduces protein synthesis and cell-surface expression of GLUT4.\",\n      \"method\": \"Yeast two-hybrid, confocal immunofluorescence co-localization, overexpression functional assay\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid and co-localization with functional consequence, single lab\",\n      \"pmids\": [\"16647043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STRAP is S-nitrosylated by iNOS specifically at Cys152 and Cys270 (the same residues required for ASK1 interaction), which disrupts the STRAP-ASK1 interaction, increases ASK1 activity, activates MKK3-p38 pathway, and enhances hydrogen peroxide-induced apoptosis. STRAP-C152/270S mutation constitutively activates the ASK1-MKK3-p38 pathway.\",\n      \"method\": \"S-nitrosylation assay, mutagenesis, Co-immunoprecipitation, kinase activity assay, apoptosis assay\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — novel PTM identified with mutagenesis, biochemical reconstitution, and clear mechanistic pathway\",\n      \"pmids\": [\"41519199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP38 stabilizes STRAP via deubiquitination, thereby enhancing TGF-β/SMAD signaling and promoting atrial fibrosis in CKD-associated atrial fibrillation. STRAP knockdown reversed the pro-fibrotic effects induced by USP38 overexpression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, KO and TG mouse models, immunofluorescence\",\n      \"journal\": \"Molecular Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — identified deubiquitinase with functional genetic validation in mouse models\",\n      \"pmids\": [\"40514673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In C. elegans neurons, TTC5 (ttc-5) is required to recruit γ-tubulin to endosomal puncta (non-centrosomal MTOCs) for microtubule nucleation. Loss of ttc-5 reduces MT numbers similarly to γ-tubulin depletion and is essential for axon regeneration, where TTC5 directs γ-tubulin to the growth cone.\",\n      \"method\": \"C. elegans genetics, conditional single-cell degradation alleles, endogenous tagging, live imaging, axon regeneration assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by live imaging with functional consequence in genetic model, preprint\",\n      \"pmids\": [\"41279556\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of TTC5-dependent tubulin autoregulation elevates soluble tubulin levels and induces microtubule hyperstability, disrupting cytoskeletal organization. This impairs localization of adhesion molecules at cell-cell junctions and extracellular matrix interfaces, compromising tissue architecture and reducing cell viability in human 3D cellular models.\",\n      \"method\": \"Human 3D cellular models, advanced optics, genetic perturbation, functional tissue assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic perturbation with specific cellular phenotype and mechanistic pathway, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.07.28.667019\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"circPCNXL2 directly binds to STRAP and induces the interaction between STRAP and MEK1/2, resulting in activation of ERK/MAPK pathway and promoting ICC tumor growth and metastasis.\",\n      \"method\": \"RNA pulldown, mass spectrometry, RIP, Co-immunoprecipitation, functional cell and in vivo assays\",\n      \"journal\": \"Molecular Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RNA pulldown with MS and functional validation, single lab\",\n      \"pmids\": [\"38365721\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TTC5 (STRAP) is a tetratricopeptide repeat/OB-fold scaffold protein with dual molecular functions: (1) as a tubulin-specific cotranslational quality control factor that binds near the ribosome exit tunnel to recognize nascent tubulin N-termini and trigger mRNA deadenylation/degradation in response to excess soluble αβ-tubulins (which normally sequester TTC5 via its flexible C-terminal tail to keep it inactive), and (2) as a multifunctional scaffold in numerous signaling pathways including TGF-β/Smad, p53/p300, Wnt/β-catenin, NF-κB/TLR, and mRNA translation/splicing regulation, operating through direct protein-protein interactions with TβR-I/II, Smad7, p53, GSK3β, ATP synthase, eIF4A, U2 snRNP components, and the Csde1 RNA-binding complex.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TTC5 (also known as STRAP) is a TPR/OB-fold scaffold protein that functions as a tubulin-specific cotranslational quality control factor and as a multivalent signaling adaptor across several major cellular pathways. In its tubulin autoregulatory role, TTC5 binds near the ribosome exit tunnel to recognize nascent tubulin N-termini and triggers tubulin mRNA degradation when soluble αβ-tubulin levels are elevated; under basal conditions, soluble tubulins sequester TTC5 via its flexible C-terminal tail, keeping this activity suppressed, and loss of this autoregulation causes chromosome segregation defects [PMID:31727855, PMID:39551769]. As a signaling scaffold, TTC5 inhibits TGF-β signaling by recruiting Smad7 to activated type I receptors [PMID:9856985, PMID:10757800], potentiates p53 transcriptional activity by displacing Mdm2 and localizing to chromatin of p53 target genes under DNA damage-induced ATM/Chk2 phosphorylation [PMID:17916563, PMID:18833288, PMID:22362889], promotes Wnt/β-catenin signaling by binding GSK3β to protect β-catenin from destruction complex-mediated degradation [PMID:26910283], and participates in U2 snRNP assembly to regulate alternative splicing of transcripts critical for nervous system development [PMID:33230114]. TTC5 also forms a complex with Csde1 to couple mRNA decay with translation, as demonstrated for Bach2 mRNA during plasma cell differentiation [PMID:40133358], and negatively regulates autophagy by antagonizing JMY-mediated actin nucleation at phagophore membranes [PMID:30593260].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identification of TTC5 (STRAP) as a TGF-β receptor-interacting protein established it as a negative regulator of TGF-β signaling, opening investigation into its scaffold function.\",\n      \"evidence\": \"Yeast two-hybrid screen and co-immunoprecipitation with TβR-I/II plus transcriptional reporter assays in mammalian cells\",\n      \"pmids\": [\"9856985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of inhibition at the receptor level was not defined\", \"No structural data on how STRAP contacts the receptors\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"The mechanism of TGF-β inhibition was resolved: STRAP recruits Smad7 specifically to the activated type I receptor, forming a ternary complex that blocks Smad2/3 access, and STRAP itself is phosphorylated in a receptor kinase-dependent manner.\",\n      \"evidence\": \"Co-immunoprecipitation showing ternary complex, reporter assays, in vivo phosphorylation analysis\",\n      \"pmids\": [\"10757800\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the specific phosphorylated residue on STRAP was not mapped\", \"In vivo relevance in animal models was not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery that TTC5 directly binds p53's DNA-binding domain and displaces Mdm2 established a second major signaling axis — p53 activation — mechanistically distinct from TGF-β inhibition.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, cysteine mutagenesis (Cys152/Cys270 on STRAP, Cys135 on p53), reporter and apoptosis assays\",\n      \"pmids\": [\"17916563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural basis for STRAP-p53 interaction\", \"Relevance in DNA damage context not yet tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The DNA damage-responsive regulation of TTC5 was established: ATM phosphorylation drives nuclear accumulation by blocking export, while Chk2 phosphorylation stabilizes nuclear TTC5, explaining how p53 coactivation is triggered by genotoxic stress.\",\n      \"evidence\": \"In vitro kinase assays, subcellular fractionation, protein stability assays\",\n      \"pmids\": [\"18833288\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact phosphorylation sites on STRAP were not all mapped\", \"Genetic epistasis in vivo was not performed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Binding of TTC5 to GSK3β and Axin, and stabilization of Notch3 intracellular domain via reduced ubiquitination, linked TTC5 to Wnt and Notch signaling pathways beyond TGF-β and p53.\",\n      \"evidence\": \"Co-immunoprecipitation and in vivo ubiquitination assays with GSK3β inhibitor controls\",\n      \"pmids\": [\"21502811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for GSK3β interaction not determined\", \"Wnt pathway functional consequences not shown in this study\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The crystal structure of full-length TTC5 at 2.05 Å revealed an atypical six-TPR plus OB-fold architecture, explaining its capacity for diverse protein–protein and protein–DNA interactions, and both domains were shown to localize to chromatin of p53 target genes.\",\n      \"evidence\": \"X-ray crystallography, ChIP assays, functional mutagenesis\",\n      \"pmids\": [\"22362889\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal structures with any binding partner\", \"How each domain individually contributes to different signaling axes was not dissected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"TTC5 was shown to regulate collagen biosynthesis by tethering to collagen mRNAs via LARP6 and restraining translation of collagen α2(I) mRNA through interaction with eIF4A, revealing a translational regulatory function.\",\n      \"evidence\": \"Co-immunoprecipitation, polysome profiling, pulldown, functional rescue in STRAP-deficient cells\",\n      \"pmids\": [\"23918805\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TTC5 directly contacts mRNA or only acts through LARP6 was not resolved\", \"Structural basis of eIF4A interaction unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"TTC5 was established as a scaffold in innate immune signaling: it bridges TAK1, IKKα, and NF-κB p65 to facilitate p65 phosphorylation and nuclear translocation in TLR2/4 pathways, with subsequent nuclear TTC5 prolonging cytokine transcription.\",\n      \"evidence\": \"Co-immunoprecipitation, knockdown/overexpression with cytokine measurement, nuclear translocation assay\",\n      \"pmids\": [\"27934954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"No structural basis for multi-protein scaffold assembly\", \"Relative contribution vs. other NF-κB scaffolds not assessed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Functional demonstration that TTC5 promotes Wnt/β-catenin signaling by binding GSK3β and preventing β-catenin phosphorylation and degradation, with consequences for CRC metastasis, extended the GSK3β interaction to a defined oncogenic pathway.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitylation assay, in vitro and in vivo metastasis assays\",\n      \"pmids\": [\"26910283\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study\", \"Whether TTC5 competes with Axin for GSK3β binding was not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A paradigm shift: TTC5 was identified as a tubulin-specific ribosome-associated quality control factor that binds near the exit tunnel, recognizes nascent tubulin N-termini, and triggers cotranslational mRNA degradation, with loss-of-function causing chromosome segregation defects.\",\n      \"evidence\": \"Structural analysis, in vitro biochemistry, mutagenesis ablating ribosome and nascent-chain interactions, mitotic phenotyping\",\n      \"pmids\": [\"31727855\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking TTC5-nascent tubulin recognition to mRNA deadenylation machinery not defined\", \"Whether other nascent chains besides tubulins are recognized was not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"TTC5 was shown to negatively regulate autophagy by binding JMY and antagonizing its LC3-dependent recruitment to phagophore membranes and actin nucleation activity.\",\n      \"evidence\": \"In vitro reconstitution with membrane-bound LC3, co-immunoprecipitation, actin polymerization assay\",\n      \"pmids\": [\"30593260\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance to autophagic flux not demonstrated in animal models\", \"Whether TTC5-JMY interaction is regulated by tubulin levels is unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"TTC5 was established as a spliceosome-associated factor involved in 17S U2 snRNP assembly; its deletion caused widespread alternative splicing changes preferentially targeting nervous system transcripts, and loss in Xenopus impaired neural tube closure.\",\n      \"evidence\": \"eCLIP-seq, RNA-seq splicing analysis, mouse embryoid body deletion model, Xenopus loss-of-function\",\n      \"pmids\": [\"33230114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RNA-binding specificity of TTC5 versus indirect recruitment via U2 snRNP not resolved\", \"Whether the splicing function is independent of the tubulin autoregulation role is unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The autoregulatory switch mechanism was resolved: soluble αβ-tubulins sequester TTC5 via its flexible C-terminal tail under normal conditions, preventing constitutive engagement of nascent tubulins at ribosomes; loss of this sequestration constitutively activates TTC5 and depletes tubulin mRNAs.\",\n      \"evidence\": \"Cryo-EM/structural proteomics, biochemical reconstitution, functional cell biology assays\",\n      \"pmids\": [\"39551769\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the deadenylase/decay machinery recruited by active TTC5 remains unknown\", \"Whether other factors modulate the C-terminal tail switch is untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The Csde1–TTC5 complex was shown to couple Bach2 mRNA decay with translation during plasma cell differentiation, establishing TTC5 as a component of a post-transcriptional regulatory module controlling immune cell fate decisions.\",\n      \"evidence\": \"RNA interactome capture, CRISPR functional screen, RIP, RNA-seq, protein stability assays in B cells\",\n      \"pmids\": [\"40133358\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TTC5 contributes RNA-binding activity or acts solely as a scaffold within the Csde1 complex is not resolved\", \"Generality to other Csde1-regulated transcripts beyond Bach2 not tested systematically\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"S-nitrosylation of TTC5 at Cys152 and Cys270 by iNOS was identified as a regulatory switch that disrupts TTC5-ASK1 interaction, activating the ASK1-MKK3-p38 apoptotic pathway, revealing redox-dependent control of TTC5 scaffold function.\",\n      \"evidence\": \"S-nitrosylation assay, cysteine mutagenesis, co-immunoprecipitation, kinase activity assay, apoptosis assay\",\n      \"pmids\": [\"41519199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contexts in which iNOS-mediated S-nitrosylation of TTC5 is triggered are not defined\", \"Interplay between S-nitrosylation and other PTMs at the same cysteines is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the identity of the mRNA decay machinery recruited by TTC5 during tubulin autoregulation; whether the tubulin quality control and signaling scaffold functions operate through the same structural surfaces or are mutually exclusive; and whether TTC5's splicing role is mechanistically linked to its translational regulatory activities.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No reconstitution of the complete tubulin autoregulation pathway from TTC5 to deadenylation/decay factors\", \"Structural basis for simultaneous engagement of multiple partners is unknown\", \"Functional hierarchy among TTC5's diverse roles in vivo has not been established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 3, 10, 11, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 7, 21, 25]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [13, 22, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 17]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4, 5, 14, 17]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 10, 11, 14, 15, 31]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6, 8, 9, 27]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 13, 23]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 15]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 25]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"complexes\": [\n      \"Csde1-Strap complex\",\n      \"17S U2 snRNP\"\n    ],\n    \"partners\": [\n      \"TGFBR1\",\n      \"SMAD7\",\n      \"TP53\",\n      \"GSK3B\",\n      \"CSDE1\",\n      \"JMY\",\n      \"LARP6\",\n      \"MAP3K5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}