{"gene":"PPIL6","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":2025,"finding":"PPIL6 was identified as a critical component of the radial spoke 1 (RS1) head-neck complex in human and mouse sperm flagella. Specifically, PPIL6 was shown to assemble into the RS1 head-neck complex together with DYDC1, NME5, and DNAJB13. Loss of IQUB caused deficiency of RS1 (but not RS2 or RS3) and was accompanied by down-regulation of PPIL6 among other RS1 components, establishing PPIL6's position within the RS1 macromolecular architecture.","method":"Protein mass spectrometry, western blotting, and bioinformatic structural modeling of RS1 components in IQUB-deficient patient sperm and Iqub-/- mice","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 — MS-based identification of complex components with functional validation in patient and mouse KO, single study","pmids":["39849482"],"is_preprint":false},{"year":2010,"finding":"PPIL6 was characterized as a member of the human cyclophilin family of peptidyl-prolyl isomerases. Enzymatic activity assays across 15 of 17 human cyclophilin isomerase domains were performed; PPIL6's isomerase domain was assessed for PPIase activity and cyclosporin-binding competence. Structural analysis revealed that regions outside the proline-binding surface impart isoform specificity, and a substrate-binding S2 position was identified as a site of diversity across the family.","method":"Enzymatic activity assay (PPIase activity), crystallographic structure determination, cyclosporin-binding assay, computational substrate-docking simulations","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro enzymatic assay and crystal structures, but PPIL6-specific activity data within a family-wide study; isoform-specific conclusions for PPIL6 are not fully elaborated","pmids":["20676357"],"is_preprint":false}],"current_model":"PPIL6 is a cyclophilin-family peptidyl-prolyl isomerase that localizes to the radial spoke 1 (RS1) head-neck complex of axonemal structures (sperm flagella and likely airway cilia), where it assembles with DYDC1, NME5, and DNAJB13 to support RS1 integrity and ciliary/flagellar beat regulation."},"narrative":{"teleology":[{"year":2010,"claim":"Establishing PPIL6 as a cyclophilin-family member resolved whether its isomerase domain possesses PPIase activity and cyclosporin-binding capacity, placing it within the broader functional landscape of human peptidyl-prolyl isomerases.","evidence":"Enzymatic PPIase activity assay, crystal structure determination, and cyclosporin-binding assay across 17 human cyclophilin domains","pmids":["20676357"],"confidence":"Medium","gaps":["PPIL6-specific catalytic activity was not elaborated in detail beyond the family-wide survey","No physiological substrate or binding partner was identified","Cellular context of PPIL6 function was not addressed"]},{"year":2025,"claim":"Identification of PPIL6 as a component of the RS1 head-neck complex in sperm flagella answered where in the cell and in what macromolecular assembly PPIL6 operates, linking a cyclophilin-family protein to axonemal radial spoke architecture.","evidence":"Mass spectrometry, western blotting, and structural modeling in IQUB-deficient patient sperm and Iqub-knockout mice","pmids":["39849482"],"confidence":"Medium","gaps":["Single study; independent replication in a separate cohort or model system is lacking","Whether PPIL6 contributes catalytic isomerase activity or serves a purely structural role within RS1 is unknown","Role of PPIL6 in motile cilia outside of sperm (e.g., airway cilia) has not been directly tested"]},{"year":null,"claim":"Whether PPIL6 functions catalytically within the RS1 complex, what its specific substrates are, and whether its loss alone causes ciliary or flagellar motility defects remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No PPIL6-specific knockout or knockdown study exists","No direct enzymatic substrate has been identified in vivo","Structural position of PPIL6 within the RS1 complex has not been resolved at atomic resolution"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0]}],"pathway":[],"complexes":[],"partners":["DYDC1","NME5","DNAJB13","IQUB"],"other_free_text":[]},"mechanistic_narrative":"PPIL6 is a cyclophilin-family protein whose isomerase domain has been structurally characterized alongside other human cyclophilins, with regions outside the proline-binding surface conferring isoform specificity [PMID:20676357]. PPIL6 assembles into the radial spoke 1 (RS1) head-neck complex of sperm flagella together with DYDC1, NME5, and DNAJB13, and its abundance depends on the RS1 scaffold protein IQUB, establishing it as a structural component of the axonemal radial spoke machinery [PMID:39849482]."},"prefetch_data":{"uniprot":{"accession":"Q8IXY8","full_name":"Probable inactive peptidyl-prolyl cis-trans isomerase-like 6","aliases":["Cyclophilin-like protein PPIL6","Rotamase PPIL6"],"length_aa":311,"mass_kda":35.2,"function":"Probable inactive PPIase with no peptidyl-prolyl cis-trans isomerase activity","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q8IXY8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PPIL6","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PPIL6","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"fallopian tube","ntpm":33.5},{"tissue":"testis","ntpm":17.5}],"url":"https://www.proteinatlas.org/search/PPIL6"},"hgnc":{"alias_symbol":["bA425D10.6","MGC41939","dJ919F19.1","RSPH12"],"prev_symbol":[]},"alphafold":{"accession":"Q8IXY8","domains":[{"cath_id":"3.40.30","chopping":"25-136","consensus_level":"high","plddt":93.4688,"start":25,"end":136},{"cath_id":"2.40.100.10","chopping":"140-306","consensus_level":"high","plddt":97.4552,"start":140,"end":306}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IXY8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IXY8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IXY8-F1-predicted_aligned_error_v6.png","plddt_mean":92.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PPIL6","jax_strain_url":"https://www.jax.org/strain/search?query=PPIL6"},"sequence":{"accession":"Q8IXY8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IXY8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IXY8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IXY8"}},"corpus_meta":[{"pmid":"39104315","id":"PMC_39104315","title":"Obesity impairs ciliary function and mucociliary clearance in the murine airway epithelium.","date":"2024","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/39104315","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39849482","id":"PMC_39849482","title":"IQUB mutation induces radial spoke 1 deficiency causing asthenozoospermia with normal sperm morphology in humans and mice.","date":"2025","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/39849482","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"42039472","id":"PMC_42039472","title":"Single-cell full-length transcriptome of human lung reveals genetic effects on isoform regulation beyond gene-level expression.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42039472","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18391951","id":"PMC_18391951","title":"Many sequence variants affecting diversity of adult human height.","date":"2008","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18391951","citation_count":520,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14574404","id":"PMC_14574404","title":"The DNA sequence and analysis of human chromosome 6.","date":"2003","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/14574404","citation_count":242,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20676357","id":"PMC_20676357","title":"Structural and biochemical characterization of the human cyclophilin family of peptidyl-prolyl isomerases.","date":"2010","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/20676357","citation_count":238,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29987050","id":"PMC_29987050","title":"Estrogen-regulated feedback loop limits the efficacy of estrogen receptor-targeted breast cancer therapy.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29987050","citation_count":59,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29676528","id":"PMC_29676528","title":"E3 ubiquitin ligase RNF123 targets lamin B1 and lamin-binding proteins.","date":"2018","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/29676528","citation_count":33,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34535262","id":"PMC_34535262","title":"Basic pH reversed-phase liquid chromatography (bRPLC) in combination with tip-based strong cation exchange (SCX-Tip), ReST, an efficient approach for large-scale cross-linked peptide analysis.","date":"2021","source":"Analytica chimica acta","url":"https://pubmed.ncbi.nlm.nih.gov/34535262","citation_count":11,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3416,"output_tokens":331,"usd":0.007607},"stage2":{"model":"claude-opus-4-6","input_tokens":3476,"output_tokens":658,"usd":0.050745},"total_usd":0.139329,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":8184,"output_tokens":695,"usd":0.017489},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":4110,"output_tokens":871,"usd":0.063488}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"PPIL6 was identified as a component of the radial spoke 1 (RS1) head-neck complex in human and mouse sperm flagella, specifically assembling into the head-neck complex together with DYDC1, NME5, and DNAJB13, as demonstrated by protein mass spectrometry and bioinformatic structural modeling in the context of IQUB deficiency.\",\n      \"method\": \"Protein mass spectrometry, western blotting, bioinformatic structural modeling, and analysis of Iqub-/- mice showing selective RS1 deficiency\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mass spectrometry identification of RS1 components with functional validation in knockout model, single study\",\n      \"pmids\": [\"39849482\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPIL6 is a structural component of the radial spoke 1 (RS1) head-neck complex in cilia and sperm flagella, where it assembles together with DYDC1, NME5, and DNAJB13 to support RS1 integrity and proper flagellar beat regulation.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"PPIL6 was identified as a critical component of the radial spoke 1 (RS1) head-neck complex in human and mouse sperm flagella. Specifically, PPIL6 was shown to assemble into the RS1 head-neck complex together with DYDC1, NME5, and DNAJB13. Loss of IQUB caused deficiency of RS1 (but not RS2 or RS3) and was accompanied by down-regulation of PPIL6 among other RS1 components, establishing PPIL6's position within the RS1 macromolecular architecture.\",\n      \"method\": \"Protein mass spectrometry, western blotting, and bioinformatic structural modeling of RS1 components in IQUB-deficient patient sperm and Iqub-/- mice\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MS-based identification of complex components with functional validation in patient and mouse KO, single study\",\n      \"pmids\": [\"39849482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PPIL6 was characterized as a member of the human cyclophilin family of peptidyl-prolyl isomerases. Enzymatic activity assays across 15 of 17 human cyclophilin isomerase domains were performed; PPIL6's isomerase domain was assessed for PPIase activity and cyclosporin-binding competence. Structural analysis revealed that regions outside the proline-binding surface impart isoform specificity, and a substrate-binding S2 position was identified as a site of diversity across the family.\",\n      \"method\": \"Enzymatic activity assay (PPIase activity), crystallographic structure determination, cyclosporin-binding assay, computational substrate-docking simulations\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay and crystal structures, but PPIL6-specific activity data within a family-wide study; isoform-specific conclusions for PPIL6 are not fully elaborated\",\n      \"pmids\": [\"20676357\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PPIL6 is a cyclophilin-family peptidyl-prolyl isomerase that localizes to the radial spoke 1 (RS1) head-neck complex of axonemal structures (sperm flagella and likely airway cilia), where it assembles with DYDC1, NME5, and DNAJB13 to support RS1 integrity and ciliary/flagellar beat regulation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PPIL6 is a structural component of the radial spoke 1 (RS1) head-neck complex in cilia and sperm flagella, where it assembles together with DYDC1, NME5, and DNAJB13 to support RS1 integrity [PMID:39849482]. Loss of the RS1 assembly factor IQUB leads to selective RS1 deficiency and concurrent loss of PPIL6 from the axoneme, linking PPIL6 to proper flagellar beat regulation [PMID:39849482].\",\n  \"teleology\": [\n    {\n      \"year\": 2025,\n      \"claim\": \"Establishing that PPIL6 is a structural subunit of the RS1 head-neck complex resolved its molecular context within the ciliary axoneme and linked it to flagellar motility regulation.\",\n      \"evidence\": \"Protein mass spectrometry and structural modeling in Iqub-knockout mouse sperm flagella\",\n      \"pmids\": [\"39849482\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study; independent confirmation of PPIL6 as an RS1 component is lacking\",\n        \"No direct loss-of-function data for PPIL6 itself (only inferred from IQUB knockout)\",\n        \"Enzymatic activity of the cyclophilin-like domain within the RS1 complex has not been tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether PPIL6 contributes catalytic peptidyl-prolyl isomerase activity to RS1 assembly or functions purely as a structural scaffold remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No PPIL6-specific knockout or mutation phenotype reported\",\n        \"No biochemical reconstitution of the RS1 head-neck complex\",\n        \"Role of PPIL6 in motile cilia outside the sperm flagellum has not been examined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"Radial spoke 1 (RS1) head-neck complex\"],\n    \"partners\": [\"DYDC1\", \"NME5\", \"DNAJB13\", \"IQUB\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PPIL6 is a cyclophilin-family protein whose isomerase domain has been structurally characterized alongside other human cyclophilins, with regions outside the proline-binding surface conferring isoform specificity [PMID:20676357]. PPIL6 assembles into the radial spoke 1 (RS1) head-neck complex of sperm flagella together with DYDC1, NME5, and DNAJB13, and its abundance depends on the RS1 scaffold protein IQUB, establishing it as a structural component of the axonemal radial spoke machinery [PMID:39849482].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Establishing PPIL6 as a cyclophilin-family member resolved whether its isomerase domain possesses PPIase activity and cyclosporin-binding capacity, placing it within the broader functional landscape of human peptidyl-prolyl isomerases.\",\n      \"evidence\": \"Enzymatic PPIase activity assay, crystal structure determination, and cyclosporin-binding assay across 17 human cyclophilin domains\",\n      \"pmids\": [\"20676357\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"PPIL6-specific catalytic activity was not elaborated in detail beyond the family-wide survey\",\n        \"No physiological substrate or binding partner was identified\",\n        \"Cellular context of PPIL6 function was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identification of PPIL6 as a component of the RS1 head-neck complex in sperm flagella answered where in the cell and in what macromolecular assembly PPIL6 operates, linking a cyclophilin-family protein to axonemal radial spoke architecture.\",\n      \"evidence\": \"Mass spectrometry, western blotting, and structural modeling in IQUB-deficient patient sperm and Iqub-knockout mice\",\n      \"pmids\": [\"39849482\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study; independent replication in a separate cohort or model system is lacking\",\n        \"Whether PPIL6 contributes catalytic isomerase activity or serves a purely structural role within RS1 is unknown\",\n        \"Role of PPIL6 in motile cilia outside of sperm (e.g., airway cilia) has not been directly tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether PPIL6 functions catalytically within the RS1 complex, what its specific substrates are, and whether its loss alone causes ciliary or flagellar motility defects remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No PPIL6-specific knockout or knockdown study exists\",\n        \"No direct enzymatic substrate has been identified in vivo\",\n        \"Structural position of PPIL6 within the RS1 complex has not been resolved at atomic resolution\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"DYDC1\", \"NME5\", \"DNAJB13\", \"IQUB\"],\n    \"other_free_text\": []\n  }\n}\n```"}