{"gene":"SMYD5","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":2017,"finding":"SMYD5 mediates trimethylation of histone H4 lysine 20 (H4K20me3) at heterochromatin regions in embryonic stem cells; knockdown of SMYD5 leads to global decrease of H4K20me3 levels, redistribution of H3K9me3/2, G9a, and HP1α, and de-repression of endogenous retroelements, compromising ES cell self-renewal.","method":"shRNA knockdown, ChIP-seq, quantitative western blot, immunofluorescence","journal":"Epigenetics & chromatin","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP-seq, western blot, gene expression), replicated in two papers from same lab","pmids":["28250819"],"is_preprint":false},{"year":2017,"finding":"SMYD5 maintains chromosome integrity by regulating H4K20me3 and H3K9me3 at heterochromatin; depletion of SMYD5 during ES cell differentiation causes chromosomal aberrations, de-repression of LTR and LINE repetitive elements, and formation of transformed cells with cancer-like expression signatures.","method":"shRNA knockdown, ChIP-seq, cytogenetic analysis, gene expression profiling","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, consistent with companion paper, defined chromosomal phenotype","pmids":["28951459"],"is_preprint":false},{"year":2022,"finding":"SMYD5 catalyzes H3K36me3 at gene promoters (distinct from SETD2-mediated H3K36me3 at gene bodies); SMYD5 is recruited to chromatin by RNA Polymerase II, and its enzymatic activity requires its C-terminal glutamic acid-rich domain, as C-terminal truncation abolishes H3K36me3 restoration at promoters.","method":"ChIP-seq, SMYD5 knockout cells, domain-truncation overexpression rescue, in vitro methyltransferase assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic assay with domain mutagenesis, KO rescue, ChIP-seq; multiple orthogonal methods in single study","pmids":["35680905"],"is_preprint":false},{"year":2022,"finding":"SMYD5 physically interacts with PGC-1α (co-immunoprecipitation), mediates lysine methylation of PGC-1α (in vitro methylation assay + mass spectrometry identification of methylated lysines), and this methylation facilitates PGC-1α ubiquitination and proteasomal degradation, attenuating mitochondrial biogenesis and respiration in intestinal epithelial cells.","method":"Co-immunoprecipitation, in vitro methylation assay, mass spectrometry, cycloheximide chase assay, conditional knockout mouse model, Seahorse respirometry","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro methylation + MS identification of sites + KO mouse model + functional readouts; multiple orthogonal methods","pmids":["35643234"],"is_preprint":false},{"year":2024,"finding":"SMYD5 is the principal methyltransferase that trimethylates ribosomal protein RPL40 at lysine 22 (rpL40K22me3); this modification regulates mRNA translation output and ribosome elongation, as SMYD5 loss leads to increased ribosome collisions and reduced translation; identified by biochemical-proteomics strategy across diverse samples.","method":"Biochemical proteomics, in vitro methyltransferase assay, ribosome profiling, SMYD5 ablation in cell lines and mouse models, patient-derived xenograft","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — robust in vitro activity, proteomics substrate identification, in vivo mouse models, replicated in independent concurrent study","pmids":["39048817"],"is_preprint":false},{"year":2024,"finding":"SMYD5 catalyzes RPL40 K22me3 in vitro and in cells; loss of SMYD5 reduces translation output and causes ribosome elongation defects (increased ribosome collisions) and decreased polysome levels; SMYD5 requires a KXY motif for substrate recognition, and does not methylate histones in vitro.","method":"In vitro methyltransferase assay with recombinant SMYD5, active-site mutagenesis, SMYD5 knockout (K562 cells), mass spectrometry, polysome profiling, systematic motif analysis","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro activity, active-site mutagenesis, KO cells, polysome profiling; replicated across two concurrent independent studies","pmids":["39103523"],"is_preprint":false},{"year":2025,"finding":"SMYD5 trimethylates RPL40/eL40 at lysine 22 through recognition of a KXY motif; active-site mutations ablate this activity; SMYD5 KO causes complete loss of RPL40 K22me3 and decreased polysome levels; SMYD5 does not methylate histones in vitro, explaining its substrate specificity divergence from other SMYD family members.","method":"In vitro methyltransferase assay with recombinant SMYD5 and synthetic RPL40, active-site mutagenesis, SMYD5 KO (K562 cells), mass spectrometry, systematic motif scanning, polysome profiling","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 — reconstitution, mutagenesis, KO, motif analysis; strong mechanistic evidence in single study","pmids":["40184250"],"is_preprint":false},{"year":2023,"finding":"SMYD5 binds the HIV-1 TAR element RNA and Tat protein, methylates Tat in vitro, associates with the HIV-1 promoter in vivo, and is required for HIV-1 transcription in CD4+ T cells; Tat expression increases SMYD5 protein levels via USP11-dependent stabilization.","method":"Co-immunoprecipitation, in vitro methylation assay, chromatin immunoprecipitation (ChIP), shRNA knockdown in cell lines and primary T cells, flow cytometry","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP, CoIP, in vitro methylation, KD), single lab study","pmids":["36897778"],"is_preprint":false},{"year":2024,"finding":"SMYD5 represses the MHR gene SP1 at euthermia; this repression correlates with temperature-dependent H3K36me3 levels at the SP1 locus; CRISPR screen identified SMYD5 as regulator of 37+ temperature-dependent genes, suggesting SMYD5-mediated H3K36me3 integrates temperature cues into gene expression.","method":"Forward CRISPR-Cas9 mutagenesis screen, ChIP-seq (H3K36me3), gene expression analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR screen plus ChIP-seq correlation, single lab, functional link established via KO","pmids":["39083378"],"is_preprint":false},{"year":2016,"finding":"Loss-of-function of Smyd5 in zebrafish (morpholino and CRISPR/Cas9) leads to increased expression of primitive and definitive hematopoietic markers (pu.1, mpx, l-plastin, cmyb), demonstrating a role for Smyd5 in hematopoiesis without affecting gross morphology, heart, or skeletal muscle development.","method":"Morpholino knockdown, CRISPR/Cas9 knockout in zebrafish, in situ hybridization for hematopoietic markers","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — two independent loss-of-function approaches (MO + CRISPR) with specific hematopoietic phenotype in zebrafish ortholog","pmids":["27377701"],"is_preprint":false},{"year":2021,"finding":"SMYD5 physically interacts with protamine (a sperm chromatin-condensing protein); the C-terminal poly-glutamic acid tract and a 30-residue insertion in the MYND domain regulate SMYD5 structural stability, but protamine binding dominates stability and overrides these effects; interaction is SMYD5-specific (SMYD2 is destabilized by protamine).","method":"Thermal shift assay, machine learning stability screening (Silver Bullets Bio library), orthogonal partial least squares regression, biochemical binding assay","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 — stability/binding assay with no functional cellular validation; single lab, single method class","pmids":["33676231"],"is_preprint":false},{"year":2024,"finding":"SMYD5 mediates methylation of FoxO1, leading to its ubiquitination and accelerated degradation, thereby promoting fibroblast-like synoviocyte (FLS) proliferation; SMYD5 also upregulates HK2 expression to promote lactate release and NF-κB activation in FLS, driving inflammatory responses in rheumatoid arthritis.","method":"Co-immunoprecipitation, in vitro methylation assay, loss-of-function/gain-of-function experiments in FLS, AAV-mediated knockdown in CIA mouse model, proteomic screening","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro methylation, CoIP, KO mouse model; two distinct mechanistic pathways identified in single study","pmids":["40165083"],"is_preprint":false},{"year":2024,"finding":"SMYD5 knockdown in lung cancer cells increases SH2B3 expression by decreasing H4K20me3 levels at the SH2B3 locus, thereby inhibiting epithelial-mesenchymal transition, cell migration, and invasion.","method":"shRNA knockdown, ChIP (H4K20me3), cell migration/invasion assays, EMT marker analysis","journal":"Molecules and cells","confidence":"Low","confidence_rationale":"Tier 3 — single lab, KD with H4K20me3 ChIP showing locus-specific change; no in vitro reconstitution","pmids":["38723947"],"is_preprint":false},{"year":2025,"finding":"SMYD5 interacts with BRD4 in hepatocellular carcinoma cells; knockdown of SMYD5 inhibits HCC cell proliferation and increases apoptosis, and the SMYD5-BRD4 interaction axis is proposed as a therapeutic target.","method":"Co-immunoprecipitation (SMYD5-BRD4 interaction), functional knockdown assays, bioinformatics analysis","journal":"Pharmaceuticals (Basel, Switzerland)","confidence":"Low","confidence_rationale":"Tier 3 — single CoIP identification of interaction, no mechanistic follow-up on how the interaction functions","pmids":["40872497"],"is_preprint":false}],"current_model":"SMYD5 is a lysine methyltransferase with dual substrates: it trimethylates histone H3K36 at gene promoters (recruited by RNA Pol II, requiring its C-terminal glutamic acid-rich domain) and histone H4K20 at heterochromatin to maintain genome stability and ES cell self-renewal, while its principal non-histone substrate is the ribosomal protein RPL40 at lysine 22 (recognized via a KXY motif), where RPL40K22me3 promotes translation elongation and enhanced ribosome output; additionally, SMYD5 methylates non-histone proteins including PGC-1α (promoting its ubiquitin-dependent degradation to suppress mitochondrial biogenesis), FoxO1 (driving its degradation to promote synoviocyte proliferation), and the HIV-1 Tat protein, with SMYD5 itself stabilized post-translationally by Tat/USP11."},"narrative":{"teleology":[{"year":2016,"claim":"Establishing a developmental role: loss of Smyd5 in zebrafish expanded hematopoietic progenitor populations without affecting gross morphology, revealing that SMYD5 normally restrains hematopoiesis.","evidence":"Morpholino knockdown and CRISPR/Cas9 knockout in zebrafish with in situ hybridization for hematopoietic markers","pmids":["27377701"],"confidence":"Medium","gaps":["Mechanism linking SMYD5 methyltransferase activity to hematopoietic gene repression not identified","Mammalian hematopoietic phenotype not tested"]},{"year":2017,"claim":"Identifying the first histone substrate: SMYD5 was shown to mediate H4K20me3 at heterochromatin in ES cells, and its depletion caused retroelement de-repression, chromosomal aberrations, and loss of self-renewal, establishing SMYD5 as a guardian of heterochromatin integrity.","evidence":"shRNA knockdown with ChIP-seq, western blot, cytogenetic analysis, and gene expression profiling in mouse ES cells","pmids":["28250819","28951459"],"confidence":"High","gaps":["In vitro reconstitution of H4K20 methyltransferase activity by recombinant SMYD5 not demonstrated in these studies","Whether SMYD5 acts directly or recruits another methyltransferase for H4K20me3 was unresolved"]},{"year":2022,"claim":"Revealing a second histone mark: SMYD5 was found to catalyze H3K36me3 specifically at gene promoters (distinct from SETD2 at gene bodies), recruited by RNA Pol II and dependent on its C-terminal glutamic acid-rich domain, thereby expanding the substrate repertoire beyond H4K20.","evidence":"ChIP-seq, SMYD5 knockout cells with domain-truncation rescue, in vitro methyltransferase assay","pmids":["35680905"],"confidence":"High","gaps":["Whether promoter H3K36me3 and heterochromatic H4K20me3 are regulated by the same or different SMYD5 complexes remains unclear","Structural basis for C-terminal domain requirement not determined"]},{"year":2022,"claim":"First non-histone substrate identified: SMYD5 methylates PGC-1α, promoting its ubiquitination and degradation, thereby attenuating mitochondrial biogenesis in intestinal epithelial cells — establishing SMYD5 as a regulator of metabolic programs through non-histone methylation.","evidence":"Co-immunoprecipitation, in vitro methylation with MS site identification, cycloheximide chase, conditional KO mouse, Seahorse respirometry","pmids":["35643234"],"confidence":"High","gaps":["Specific lysine sites on PGC-1α and the E3 ligase mediating downstream ubiquitination not fully characterized","Whether this mechanism operates outside intestinal epithelium is unknown"]},{"year":2023,"claim":"Linking SMYD5 to viral transcription: SMYD5 binds HIV-1 TAR RNA and Tat protein, methylates Tat, and is required for HIV-1 transcription; reciprocally, Tat stabilizes SMYD5 via USP11, revealing a host-virus feedback loop.","evidence":"Co-immunoprecipitation, in vitro methylation, ChIP at HIV-1 promoter, shRNA knockdown in primary CD4+ T cells","pmids":["36897778"],"confidence":"Medium","gaps":["Tat methylation site(s) and their functional consequence for Tat activity not determined","Whether SMYD5's role in HIV-1 transcription depends on its methyltransferase activity versus a scaffolding function is unresolved","Single-lab finding"]},{"year":2024,"claim":"Defining the principal non-histone substrate: three independent studies converged on RPL40 K22 as the primary SMYD5 substrate, showing that SMYD5-mediated RPL40K22me3 promotes translation elongation and that SMYD5 loss causes ribosome collisions and reduced polysome levels — repositioning SMYD5 as a central translational regulator.","evidence":"Biochemical proteomics, reconstituted in vitro methyltransferase assays with active-site mutagenesis, KO in K562 cells and mouse models, ribosome profiling, polysome profiling, KXY motif analysis","pmids":["39048817","39103523","40184250"],"confidence":"High","gaps":["How RPL40K22me3 mechanistically prevents ribosome collisions at the structural level is unknown","Whether SMYD5 methylates additional ribosomal proteins or translation factors via the KXY motif is unexplored","Discrepancy between robust in vitro histone methylation in some studies and absence in others remains unresolved"]},{"year":2024,"claim":"Expanding non-histone substrates: SMYD5 methylates FoxO1, promoting its degradation and driving synoviocyte proliferation and inflammatory signaling in rheumatoid arthritis, paralleling the PGC-1α degradation mechanism.","evidence":"Co-immunoprecipitation, in vitro methylation, gain/loss-of-function in fibroblast-like synoviocytes, AAV-mediated knockdown in CIA mouse model","pmids":["40165083"],"confidence":"Medium","gaps":["FoxO1 methylation site(s) not mapped","The E3 ligase linking FoxO1 methylation to ubiquitination is unidentified","Single-lab finding"]},{"year":null,"claim":"The central unresolved question is how SMYD5 partitions its activity between histone substrates (H4K20, H3K36) and non-histone substrates (RPL40, PGC-1α, FoxO1): whether these reflect distinct subcellular pools, regulatory states, or complex-dependent targeting remains unknown.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of SMYD5 with any substrate exists","Relative physiological contribution of histone versus RPL40 methylation to SMYD5-null phenotypes not dissected","No crystal structure of SMYD5-RPL40 complex to explain KXY motif recognition"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2,3,4,5,6,7,11]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,2,7,8]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,1,2,8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,4,5,6,11]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[2,8]}],"complexes":[],"partners":["RPL40","PGC-1Α","FOXO1","USP11"],"other_free_text":[]},"mechanistic_narrative":"SMYD5 is a SET-domain lysine methyltransferase that acts on both histone and non-histone substrates to regulate chromatin silencing, gene expression, and translation. At chromatin, SMYD5 trimethylates H4K20 at heterochromatin to silence endogenous retroelements and maintain genome stability in embryonic stem cells [PMID:28250819, PMID:28951459], and trimethylates H3K36 at gene promoters through RNA Polymerase II-dependent recruitment requiring its C-terminal glutamic acid-rich domain [PMID:35680905]. The principal non-histone substrate of SMYD5 is the ribosomal protein RPL40, which it trimethylates at lysine 22 via a KXY recognition motif; loss of this modification causes ribosome collisions and reduced translation elongation [PMID:39048817, PMID:39103523, PMID:40184250]. SMYD5 also methylates non-histone proteins PGC-1α and FoxO1, promoting their ubiquitin-dependent degradation to suppress mitochondrial biogenesis and modulate synoviocyte proliferation, respectively [PMID:35643234, PMID:40165083]."},"prefetch_data":{"uniprot":{"accession":"Q6GMV2","full_name":"Protein-lysine N-trimethyltransferase SMYD5","aliases":["Protein NN8-4AG","Retinoic acid-induced protein 15","SET and MYND domain-containing protein 5","[histone H3]-lysine20 N-trimethyltransferase SMYD5","[histone H4]-lysine36 N-trimethyltransferase SMYD5"],"length_aa":418,"mass_kda":47.3,"function":"Protein-lysine N-trimethyltransferase that specifically catalyzes trimethylation of 'Lys-22' of the RPL40/eL40 subunit of the 60S ribosome, thereby promoting translation elongation and protein synthesis (PubMed:39048817, PubMed:39103523). May also act as a histone methyltransferase in the context of histone octamers, but not on nucleosome substrates: trimethylates 'Lys-36' of histone H3 and 'Lys-20' of histone H4 to form H3K36me3 and H4K20me3, respectively (By similarity). The histone methyltransferase activity, which is independent of its SET domain, is however unsure in vivo (PubMed:39048817, PubMed:39103523). In association with the NCoR corepressor complex, involved in the repression of toll-like receptor 4 (TLR4)-target inflammatory genes in macrophages, possibly by catalyzing the formation of H4K20me3 at the gene promoters (By similarity). Plays an important role in embryonic stem (ES) cell self-renewal and differentiation (By similarity). Maintains genome stability of ES cells during differentiation through regulation of heterochromatin formation and repression of endogenous repetitive DNA elements by promoting H4K20me3 marks (PubMed:28951459). Acts as a regulator of the hypothermia response: its degradation in response to mild hypothermia relieves the formation of H3K36me3 at gene promoters, allowing expression of the neuroprotective gene SP1 (By similarity)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q6GMV2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SMYD5","classification":"Not Classified","n_dependent_lines":25,"n_total_lines":1208,"dependency_fraction":0.020695364238410598},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SMYD5","total_profiled":1310},"omim":[{"mim_id":"619114","title":"SET AND MYND DOMAIN-CONTAINING PROTEIN 5; SMYD5","url":"https://www.omim.org/entry/619114"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SMYD5"},"hgnc":{"alias_symbol":["RRG1","NN8-4AG","ZMYND23"],"prev_symbol":["RAI15"]},"alphafold":{"accession":"Q6GMV2","domains":[{"cath_id":"2.170.270.10","chopping":"6-54_309-387","consensus_level":"medium","plddt":92.9402,"start":6,"end":387},{"cath_id":"-","chopping":"58-256","consensus_level":"high","plddt":91.4938,"start":58,"end":256}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6GMV2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6GMV2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6GMV2-F1-predicted_aligned_error_v6.png","plddt_mean":88.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SMYD5","jax_strain_url":"https://www.jax.org/strain/search?query=SMYD5"},"sequence":{"accession":"Q6GMV2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6GMV2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6GMV2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6GMV2"}},"corpus_meta":[{"pmid":"17392518","id":"PMC_17392518","title":"The response regulator RRG-1 functions upstream of a mitogen-activated protein kinase pathway impacting asexual development, female fertility, osmotic stress, and fungicide resistance in Neurospora crassa.","date":"2007","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/17392518","citation_count":80,"is_preprint":false},{"pmid":"28250819","id":"PMC_28250819","title":"SMYD5 regulates H4K20me3-marked heterochromatin to safeguard ES cell self-renewal and prevent spurious differentiation.","date":"2017","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/28250819","citation_count":55,"is_preprint":false},{"pmid":"35680905","id":"PMC_35680905","title":"SMYD5 catalyzes histone H3 lysine 36 trimethylation at promoters.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35680905","citation_count":37,"is_preprint":false},{"pmid":"39048817","id":"PMC_39048817","title":"SMYD5 methylation of rpL40 links ribosomal output to gastric cancer.","date":"2024","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/39048817","citation_count":30,"is_preprint":false},{"pmid":"28951459","id":"PMC_28951459","title":"SMYD5 Controls Heterochromatin and Chromosome Integrity during Embryonic Stem Cell Differentiation.","date":"2017","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/28951459","citation_count":30,"is_preprint":false},{"pmid":"27377701","id":"PMC_27377701","title":"Smyd5 plays pivotal roles in both primitive and definitive hematopoiesis during zebrafish embryogenesis.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27377701","citation_count":29,"is_preprint":false},{"pmid":"35643234","id":"PMC_35643234","title":"Epithelial SMYD5 Exaggerates IBD by Down-regulating Mitochondrial Functions via Post-Translational Control of PGC-1α Stability.","date":"2022","source":"Cellular and molecular gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/35643234","citation_count":17,"is_preprint":false},{"pmid":"36897778","id":"PMC_36897778","title":"The lysine methyltransferase SMYD5 amplifies HIV-1 transcription and is post-transcriptionally upregulated by Tat and USP11.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36897778","citation_count":14,"is_preprint":false},{"pmid":"39103523","id":"PMC_39103523","title":"SMYD5 is a ribosomal methyltransferase that catalyzes RPL40 lysine methylation to enhance translation output and promote hepatocellular carcinoma.","date":"2024","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/39103523","citation_count":13,"is_preprint":false},{"pmid":"35740908","id":"PMC_35740908","title":"Unique SMYD5 Structure Revealed by AlphaFold Correlates with Its Functional Divergence.","date":"2022","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/35740908","citation_count":11,"is_preprint":false},{"pmid":"35218722","id":"PMC_35218722","title":"SMYD5 acts as a potential biomarker for hepatocellular carcinoma.","date":"2022","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/35218722","citation_count":9,"is_preprint":false},{"pmid":"11861905","id":"PMC_11861905","title":"Glucose-inducible expression of rrg1+ in Schizosaccharomyces pombe: post-transcriptional regulation of mRNA stability mediated by the downstream region of the poly(A) site.","date":"2002","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/11861905","citation_count":6,"is_preprint":false},{"pmid":"38723947","id":"PMC_38723947","title":"Negative regulation of SH2B3 by SMYD5 controls epithelial-mesenchymal transition in lung cancer.","date":"2024","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/38723947","citation_count":5,"is_preprint":false},{"pmid":"33676231","id":"PMC_33676231","title":"Sperm chromatin-condensing protamine enhances SMYD5 thermal stability.","date":"2021","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/33676231","citation_count":5,"is_preprint":false},{"pmid":"39083378","id":"PMC_39083378","title":"SMYD5 is a regulator of the mild hypothermia response.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39083378","citation_count":2,"is_preprint":false},{"pmid":"40165083","id":"PMC_40165083","title":"Novel regulation mechanism of histone methyltransferase SMYD5 in rheumatoid arthritis.","date":"2025","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/40165083","citation_count":1,"is_preprint":false},{"pmid":"37925635","id":"PMC_37925635","title":"A flow cytometry-based assay to investigate HIV-1 expression in SMYD5 shRNA containing primary CD4+ T cells.","date":"2023","source":"STAR protocols","url":"https://pubmed.ncbi.nlm.nih.gov/37925635","citation_count":1,"is_preprint":false},{"pmid":"40872497","id":"PMC_40872497","title":"SMYD5-BRD4 Interaction Drives Hepatocellular Carcinoma Progression: A Combined in Silico and Experimental Analysis.","date":"2025","source":"Pharmaceuticals (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/40872497","citation_count":0,"is_preprint":false},{"pmid":"12442907","id":"PMC_12442907","title":"A glucose-inducible gene in Schizosaccharomyces pombe, rrg1+, is involved in negative regulation of G2/M progression.","date":"2002","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/12442907","citation_count":0,"is_preprint":false},{"pmid":"40184250","id":"PMC_40184250","title":"SMYD5 is a ribosomal methyltransferase that trimethylates RPL40 lysine 22 through recognition of a KXY motif.","date":"2025","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/40184250","citation_count":0,"is_preprint":false},{"pmid":"37333301","id":"PMC_37333301","title":"SMYD5 is a regulator of the mild hypothermia response.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37333301","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.10.616381","title":"SMYD5 is a ribosomal methyltransferase which trimethylates RPL40 lysine 22 through recognition of a KXY motif","date":"2024-10-11","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.10.616381","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11598,"output_tokens":3509,"usd":0.043715},"stage2":{"model":"claude-opus-4-6","input_tokens":6915,"output_tokens":2378,"usd":0.141038},"total_usd":0.184753,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"SMYD5 mediates trimethylation of histone H4 lysine 20 (H4K20me3) at heterochromatin regions in embryonic stem cells; knockdown of SMYD5 leads to global decrease of H4K20me3 levels, redistribution of H3K9me3/2, G9a, and HP1α, and de-repression of endogenous retroelements, compromising ES cell self-renewal.\",\n      \"method\": \"shRNA knockdown, ChIP-seq, quantitative western blot, immunofluorescence\",\n      \"journal\": \"Epigenetics & chromatin\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP-seq, western blot, gene expression), replicated in two papers from same lab\",\n      \"pmids\": [\"28250819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SMYD5 maintains chromosome integrity by regulating H4K20me3 and H3K9me3 at heterochromatin; depletion of SMYD5 during ES cell differentiation causes chromosomal aberrations, de-repression of LTR and LINE repetitive elements, and formation of transformed cells with cancer-like expression signatures.\",\n      \"method\": \"shRNA knockdown, ChIP-seq, cytogenetic analysis, gene expression profiling\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, consistent with companion paper, defined chromosomal phenotype\",\n      \"pmids\": [\"28951459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SMYD5 catalyzes H3K36me3 at gene promoters (distinct from SETD2-mediated H3K36me3 at gene bodies); SMYD5 is recruited to chromatin by RNA Polymerase II, and its enzymatic activity requires its C-terminal glutamic acid-rich domain, as C-terminal truncation abolishes H3K36me3 restoration at promoters.\",\n      \"method\": \"ChIP-seq, SMYD5 knockout cells, domain-truncation overexpression rescue, in vitro methyltransferase assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay with domain mutagenesis, KO rescue, ChIP-seq; multiple orthogonal methods in single study\",\n      \"pmids\": [\"35680905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SMYD5 physically interacts with PGC-1α (co-immunoprecipitation), mediates lysine methylation of PGC-1α (in vitro methylation assay + mass spectrometry identification of methylated lysines), and this methylation facilitates PGC-1α ubiquitination and proteasomal degradation, attenuating mitochondrial biogenesis and respiration in intestinal epithelial cells.\",\n      \"method\": \"Co-immunoprecipitation, in vitro methylation assay, mass spectrometry, cycloheximide chase assay, conditional knockout mouse model, Seahorse respirometry\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro methylation + MS identification of sites + KO mouse model + functional readouts; multiple orthogonal methods\",\n      \"pmids\": [\"35643234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SMYD5 is the principal methyltransferase that trimethylates ribosomal protein RPL40 at lysine 22 (rpL40K22me3); this modification regulates mRNA translation output and ribosome elongation, as SMYD5 loss leads to increased ribosome collisions and reduced translation; identified by biochemical-proteomics strategy across diverse samples.\",\n      \"method\": \"Biochemical proteomics, in vitro methyltransferase assay, ribosome profiling, SMYD5 ablation in cell lines and mouse models, patient-derived xenograft\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — robust in vitro activity, proteomics substrate identification, in vivo mouse models, replicated in independent concurrent study\",\n      \"pmids\": [\"39048817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SMYD5 catalyzes RPL40 K22me3 in vitro and in cells; loss of SMYD5 reduces translation output and causes ribosome elongation defects (increased ribosome collisions) and decreased polysome levels; SMYD5 requires a KXY motif for substrate recognition, and does not methylate histones in vitro.\",\n      \"method\": \"In vitro methyltransferase assay with recombinant SMYD5, active-site mutagenesis, SMYD5 knockout (K562 cells), mass spectrometry, polysome profiling, systematic motif analysis\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro activity, active-site mutagenesis, KO cells, polysome profiling; replicated across two concurrent independent studies\",\n      \"pmids\": [\"39103523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SMYD5 trimethylates RPL40/eL40 at lysine 22 through recognition of a KXY motif; active-site mutations ablate this activity; SMYD5 KO causes complete loss of RPL40 K22me3 and decreased polysome levels; SMYD5 does not methylate histones in vitro, explaining its substrate specificity divergence from other SMYD family members.\",\n      \"method\": \"In vitro methyltransferase assay with recombinant SMYD5 and synthetic RPL40, active-site mutagenesis, SMYD5 KO (K562 cells), mass spectrometry, systematic motif scanning, polysome profiling\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution, mutagenesis, KO, motif analysis; strong mechanistic evidence in single study\",\n      \"pmids\": [\"40184250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SMYD5 binds the HIV-1 TAR element RNA and Tat protein, methylates Tat in vitro, associates with the HIV-1 promoter in vivo, and is required for HIV-1 transcription in CD4+ T cells; Tat expression increases SMYD5 protein levels via USP11-dependent stabilization.\",\n      \"method\": \"Co-immunoprecipitation, in vitro methylation assay, chromatin immunoprecipitation (ChIP), shRNA knockdown in cell lines and primary T cells, flow cytometry\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, CoIP, in vitro methylation, KD), single lab study\",\n      \"pmids\": [\"36897778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SMYD5 represses the MHR gene SP1 at euthermia; this repression correlates with temperature-dependent H3K36me3 levels at the SP1 locus; CRISPR screen identified SMYD5 as regulator of 37+ temperature-dependent genes, suggesting SMYD5-mediated H3K36me3 integrates temperature cues into gene expression.\",\n      \"method\": \"Forward CRISPR-Cas9 mutagenesis screen, ChIP-seq (H3K36me3), gene expression analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR screen plus ChIP-seq correlation, single lab, functional link established via KO\",\n      \"pmids\": [\"39083378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss-of-function of Smyd5 in zebrafish (morpholino and CRISPR/Cas9) leads to increased expression of primitive and definitive hematopoietic markers (pu.1, mpx, l-plastin, cmyb), demonstrating a role for Smyd5 in hematopoiesis without affecting gross morphology, heart, or skeletal muscle development.\",\n      \"method\": \"Morpholino knockdown, CRISPR/Cas9 knockout in zebrafish, in situ hybridization for hematopoietic markers\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — two independent loss-of-function approaches (MO + CRISPR) with specific hematopoietic phenotype in zebrafish ortholog\",\n      \"pmids\": [\"27377701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SMYD5 physically interacts with protamine (a sperm chromatin-condensing protein); the C-terminal poly-glutamic acid tract and a 30-residue insertion in the MYND domain regulate SMYD5 structural stability, but protamine binding dominates stability and overrides these effects; interaction is SMYD5-specific (SMYD2 is destabilized by protamine).\",\n      \"method\": \"Thermal shift assay, machine learning stability screening (Silver Bullets Bio library), orthogonal partial least squares regression, biochemical binding assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — stability/binding assay with no functional cellular validation; single lab, single method class\",\n      \"pmids\": [\"33676231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SMYD5 mediates methylation of FoxO1, leading to its ubiquitination and accelerated degradation, thereby promoting fibroblast-like synoviocyte (FLS) proliferation; SMYD5 also upregulates HK2 expression to promote lactate release and NF-κB activation in FLS, driving inflammatory responses in rheumatoid arthritis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro methylation assay, loss-of-function/gain-of-function experiments in FLS, AAV-mediated knockdown in CIA mouse model, proteomic screening\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro methylation, CoIP, KO mouse model; two distinct mechanistic pathways identified in single study\",\n      \"pmids\": [\"40165083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SMYD5 knockdown in lung cancer cells increases SH2B3 expression by decreasing H4K20me3 levels at the SH2B3 locus, thereby inhibiting epithelial-mesenchymal transition, cell migration, and invasion.\",\n      \"method\": \"shRNA knockdown, ChIP (H4K20me3), cell migration/invasion assays, EMT marker analysis\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, KD with H4K20me3 ChIP showing locus-specific change; no in vitro reconstitution\",\n      \"pmids\": [\"38723947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SMYD5 interacts with BRD4 in hepatocellular carcinoma cells; knockdown of SMYD5 inhibits HCC cell proliferation and increases apoptosis, and the SMYD5-BRD4 interaction axis is proposed as a therapeutic target.\",\n      \"method\": \"Co-immunoprecipitation (SMYD5-BRD4 interaction), functional knockdown assays, bioinformatics analysis\",\n      \"journal\": \"Pharmaceuticals (Basel, Switzerland)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single CoIP identification of interaction, no mechanistic follow-up on how the interaction functions\",\n      \"pmids\": [\"40872497\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SMYD5 is a lysine methyltransferase with dual substrates: it trimethylates histone H3K36 at gene promoters (recruited by RNA Pol II, requiring its C-terminal glutamic acid-rich domain) and histone H4K20 at heterochromatin to maintain genome stability and ES cell self-renewal, while its principal non-histone substrate is the ribosomal protein RPL40 at lysine 22 (recognized via a KXY motif), where RPL40K22me3 promotes translation elongation and enhanced ribosome output; additionally, SMYD5 methylates non-histone proteins including PGC-1α (promoting its ubiquitin-dependent degradation to suppress mitochondrial biogenesis), FoxO1 (driving its degradation to promote synoviocyte proliferation), and the HIV-1 Tat protein, with SMYD5 itself stabilized post-translationally by Tat/USP11.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SMYD5 is a SET-domain lysine methyltransferase that acts on both histone and non-histone substrates to regulate chromatin silencing, gene expression, and translation. At chromatin, SMYD5 trimethylates H4K20 at heterochromatin to silence endogenous retroelements and maintain genome stability in embryonic stem cells [PMID:28250819, PMID:28951459], and trimethylates H3K36 at gene promoters through RNA Polymerase II-dependent recruitment requiring its C-terminal glutamic acid-rich domain [PMID:35680905]. The principal non-histone substrate of SMYD5 is the ribosomal protein RPL40, which it trimethylates at lysine 22 via a KXY recognition motif; loss of this modification causes ribosome collisions and reduced translation elongation [PMID:39048817, PMID:39103523, PMID:40184250]. SMYD5 also methylates non-histone proteins PGC-1α and FoxO1, promoting their ubiquitin-dependent degradation to suppress mitochondrial biogenesis and modulate synoviocyte proliferation, respectively [PMID:35643234, PMID:40165083].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Establishing a developmental role: loss of Smyd5 in zebrafish expanded hematopoietic progenitor populations without affecting gross morphology, revealing that SMYD5 normally restrains hematopoiesis.\",\n      \"evidence\": \"Morpholino knockdown and CRISPR/Cas9 knockout in zebrafish with in situ hybridization for hematopoietic markers\",\n      \"pmids\": [\"27377701\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking SMYD5 methyltransferase activity to hematopoietic gene repression not identified\", \"Mammalian hematopoietic phenotype not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying the first histone substrate: SMYD5 was shown to mediate H4K20me3 at heterochromatin in ES cells, and its depletion caused retroelement de-repression, chromosomal aberrations, and loss of self-renewal, establishing SMYD5 as a guardian of heterochromatin integrity.\",\n      \"evidence\": \"shRNA knockdown with ChIP-seq, western blot, cytogenetic analysis, and gene expression profiling in mouse ES cells\",\n      \"pmids\": [\"28250819\", \"28951459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro reconstitution of H4K20 methyltransferase activity by recombinant SMYD5 not demonstrated in these studies\", \"Whether SMYD5 acts directly or recruits another methyltransferase for H4K20me3 was unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealing a second histone mark: SMYD5 was found to catalyze H3K36me3 specifically at gene promoters (distinct from SETD2 at gene bodies), recruited by RNA Pol II and dependent on its C-terminal glutamic acid-rich domain, thereby expanding the substrate repertoire beyond H4K20.\",\n      \"evidence\": \"ChIP-seq, SMYD5 knockout cells with domain-truncation rescue, in vitro methyltransferase assay\",\n      \"pmids\": [\"35680905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether promoter H3K36me3 and heterochromatic H4K20me3 are regulated by the same or different SMYD5 complexes remains unclear\", \"Structural basis for C-terminal domain requirement not determined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"First non-histone substrate identified: SMYD5 methylates PGC-1α, promoting its ubiquitination and degradation, thereby attenuating mitochondrial biogenesis in intestinal epithelial cells — establishing SMYD5 as a regulator of metabolic programs through non-histone methylation.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro methylation with MS site identification, cycloheximide chase, conditional KO mouse, Seahorse respirometry\",\n      \"pmids\": [\"35643234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific lysine sites on PGC-1α and the E3 ligase mediating downstream ubiquitination not fully characterized\", \"Whether this mechanism operates outside intestinal epithelium is unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linking SMYD5 to viral transcription: SMYD5 binds HIV-1 TAR RNA and Tat protein, methylates Tat, and is required for HIV-1 transcription; reciprocally, Tat stabilizes SMYD5 via USP11, revealing a host-virus feedback loop.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro methylation, ChIP at HIV-1 promoter, shRNA knockdown in primary CD4+ T cells\",\n      \"pmids\": [\"36897778\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tat methylation site(s) and their functional consequence for Tat activity not determined\", \"Whether SMYD5's role in HIV-1 transcription depends on its methyltransferase activity versus a scaffolding function is unresolved\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defining the principal non-histone substrate: three independent studies converged on RPL40 K22 as the primary SMYD5 substrate, showing that SMYD5-mediated RPL40K22me3 promotes translation elongation and that SMYD5 loss causes ribosome collisions and reduced polysome levels — repositioning SMYD5 as a central translational regulator.\",\n      \"evidence\": \"Biochemical proteomics, reconstituted in vitro methyltransferase assays with active-site mutagenesis, KO in K562 cells and mouse models, ribosome profiling, polysome profiling, KXY motif analysis\",\n      \"pmids\": [\"39048817\", \"39103523\", \"40184250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How RPL40K22me3 mechanistically prevents ribosome collisions at the structural level is unknown\", \"Whether SMYD5 methylates additional ribosomal proteins or translation factors via the KXY motif is unexplored\", \"Discrepancy between robust in vitro histone methylation in some studies and absence in others remains unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanding non-histone substrates: SMYD5 methylates FoxO1, promoting its degradation and driving synoviocyte proliferation and inflammatory signaling in rheumatoid arthritis, paralleling the PGC-1α degradation mechanism.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro methylation, gain/loss-of-function in fibroblast-like synoviocytes, AAV-mediated knockdown in CIA mouse model\",\n      \"pmids\": [\"40165083\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FoxO1 methylation site(s) not mapped\", \"The E3 ligase linking FoxO1 methylation to ubiquitination is unidentified\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The central unresolved question is how SMYD5 partitions its activity between histone substrates (H4K20, H3K36) and non-histone substrates (RPL40, PGC-1α, FoxO1): whether these reflect distinct subcellular pools, regulatory states, or complex-dependent targeting remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of SMYD5 with any substrate exists\", \"Relative physiological contribution of histone versus RPL40 methylation to SMYD5-null phenotypes not dissected\", \"No crystal structure of SMYD5-RPL40 complex to explain KXY motif recognition\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 5, 6, 7, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 2, 7, 8]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 1, 2, 8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 4, 5, 6, 11]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [2, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RPL40\",\n      \"PGC-1α\",\n      \"FoxO1\",\n      \"USP11\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}