{"gene":"SPA17","run_date":"2026-06-10T07:46:38","timeline":{"discoveries":[{"year":2021,"finding":"Crystal structure of the SPA17 D/D domain (amino acids 1-75) resolved at 1.72 Å reveals a four-helix bundle-like configuration with terminal β-strands that mediate higher-order oligomerization. In solution, SPA17 forms both homodimers and tetramers and displays weak affinity for AKAP18 alone, but binds AKAP18 at nanomolar affinity when SPA17 heterodimerizes with the ropporin-1-like D/D protein.","method":"X-ray crystallography (1.72 Å), solution biophysics (oligomerization assays), quantitative binding affinity measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional validation (heterodimerization and AKAP18 binding quantified), single lab but multiple orthogonal methods","pmids":["34256050"],"is_preprint":false},{"year":2004,"finding":"In Akap4 knockout mice, the fibrous sheath is disrupted and the subcellular distribution of SP17 (SPA17) is altered, demonstrating that SPA17 localization in the sperm flagellum depends on AKAP4-mediated fibrous sheath integrity.","method":"Akap4 gene knockout mouse model with immunofluorescence/subcellular fractionation to assess SP17 distribution","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean genetic KO with defined localization phenotype, single lab, single method reported in abstract","pmids":["15385410"],"is_preprint":false},{"year":2022,"finding":"In yak sperm, phosphorylation of SPA17 at Y156 increases during capacitation, identifying SPA17 as a phosphorylation substrate regulated through the cAMP/PKA signaling pathway and suggesting a functional role in sperm capacitation beyond scaffold AKAPs.","method":"Quantitative phosphoproteomics (TMT labeling + LC-MS/MS) across sperm capacitation states","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — site-specific phosphorylation identified by mass spectrometry in a relevant biological context, single lab, single method","pmids":["36277216"],"is_preprint":false},{"year":2021,"finding":"During bull sperm capacitation, SPA17 undergoes reversible oxidative post-translational modifications (oxPTMs) at susceptible cysteines, linking SPA17 to redox-regulated cAMP/PKA pathway signaling during capacitation.","method":"Fluorescent gel-based redox proteomics, Western blot, flow cytometry","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct detection of oxPTMs on SPA17 using redox proteomics, single lab, moderate methodological depth","pmids":["34360666"],"is_preprint":false},{"year":2023,"finding":"In high sperm DNA fragmentation index (H-DFI) patients, SPA17 protein expression is increased while AKAP4 and PKARII are decreased; H2O2-induced oxidative stress mimics this pattern and inhibits sperm capacitation and acrosome reaction, placing SPA17 within the AKAP4/PKA signaling axis that regulates capacitation.","method":"Western blot on patient sperm samples; H2O2 oxidative stress model in sperm; IVF outcome correlation","journal":"Asian journal of andrology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional pathway placement via protein expression changes and oxidative stress model, single lab, two orthogonal approaches (patient samples + H2O2 model)","pmids":["37695244"],"is_preprint":false},{"year":2008,"finding":"Mouse RBMY protein binds to spa17 mRNA from testis; electrophoretic mobility shift assay demonstrated direct binding, with the binding domain containing rich oligo(A) sequences, suggesting mRBMY has high affinity for oligo(A)-rich sequences including spa17 mRNA.","method":"Immunoprecipitation of RNA-protein complexes from testis, electrophoretic mobility shift assay (EMSA)","journal":"Molecular human reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct RNA-protein binding demonstrated by EMSA with domain characterization, single lab","pmids":["18492746"],"is_preprint":false},{"year":2007,"finding":"SPA17 protein colocalizes with acetylated tubulin in the cilia layer of mouse olfactory epithelium, establishing SPA17 as a component of sensory cilia in olfactory sensory neurons.","method":"Immunofluorescence colocalization with acetylated tubulin in olfactory epithelium sections","journal":"Physiological genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — direct immunolocalization in tissue, single lab, single method, no functional consequence tested","pmids":["17971504"],"is_preprint":false},{"year":2018,"finding":"Treatment of human sperm with α-chymotrypsin degrades SPA17 from the sperm surface, generating a 17 kDa cleavage product (loss of C-terminal calmodulin-binding domain) from the native 20 kDa form, demonstrating that SPA17 is a surface-exposed protein with a C-terminal calmodulin-binding domain susceptible to proteolytic cleavage.","method":"Western blot analysis of α-chymotrypsin-treated sperm samples","journal":"Andrology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single biochemical experiment revealing domain structure via proteolysis, single lab, single method","pmids":["29409138"],"is_preprint":false}],"current_model":"SPA17 (sperm autoantigenic protein 17) is a sperm- and cilia-expressed protein whose D/D domain forms homodimers and tetramers and heterodimerizes with ropporin-1-like protein to bind AKAP18 at nanomolar affinity, placing it within the AKAP/PKA signaling scaffold of the sperm flagellum; its localization to the fibrous sheath depends on AKAP4 integrity, its Y156 residue is phosphorylated during capacitation via the cAMP/PKA pathway, and it undergoes redox-regulated oxPTMs during capacitation, collectively indicating that SPA17 functions as a structural and signaling scaffold protein coordinating PKA-mediated regulation of sperm capacitation and motility."},"narrative":{"mechanistic_narrative":"SPA17 (sperm autoantigenic protein 17) is a sperm- and cilia-associated scaffold protein that integrates into the AKAP/PKA signaling architecture of the sperm flagellum and coordinates redox- and phosphorylation-regulated events during capacitation [PMID:34256050, PMID:37695244]. Its N-terminal dimerization/docking (D/D) domain (residues 1-75) folds into a four-helix-bundle-like configuration whose terminal β-strands drive higher-order oligomerization; SPA17 forms homodimers and tetramers in solution and binds AKAP18 with nanomolar affinity only upon heterodimerization with the ropporin-1-like D/D protein, placing it as an AKAP-docking module rather than a free monomer [PMID:34256050]. Proper flagellar localization of SPA17 to the fibrous sheath depends on AKAP4 integrity, as Akap4 knockout disrupts the fibrous sheath and alters SPA17 distribution [PMID:15385410]. During capacitation SPA17 is a regulated target of cAMP/PKA signaling: it is phosphorylated at Y156 [PMID:36277216] and undergoes reversible oxidative modifications at susceptible cysteines [PMID:34360666], and in high-DNA-fragmentation sperm its expression rises while AKAP4 and PKARII fall, mirroring an oxidative-stress phenotype that impairs capacitation and the acrosome reaction [PMID:37695244]. SPA17 also localizes to sensory cilia of olfactory neurons, indicating a broader ciliary role beyond sperm [PMID:17971504]. The protein is surface-exposed and carries a protease-susceptible C-terminal calmodulin-binding domain [PMID:29409138], and its testicular mRNA is bound directly by the RNA-binding protein RBMY [PMID:18492746].","teleology":[{"year":2004,"claim":"Established that SPA17's flagellar positioning is not autonomous but depends on a defined structural scaffold, linking it to fibrous sheath architecture.","evidence":"Akap4 knockout mouse with immunolocalization/fractionation of SP17","pmids":["15385410"],"confidence":"Medium","gaps":["Does not show direct AKAP4-SPA17 binding versus indirect dependence on sheath integrity","Functional consequence of mislocalization for motility not measured"]},{"year":2007,"claim":"Extended SPA17 beyond sperm by placing it in sensory cilia, implying a conserved ciliary function.","evidence":"Immunofluorescence colocalization with acetylated tubulin in mouse olfactory epithelium","pmids":["17971504"],"confidence":"Medium","gaps":["No functional role in olfactory signaling tested","Mechanism of ciliary targeting unknown"]},{"year":2008,"claim":"Identified a post-transcriptional control point by showing SPA17 mRNA is a direct binding target of an RNA-binding protein in testis.","evidence":"RNP immunoprecipitation and EMSA from testis demonstrating RBMY binding to oligo(A)-rich spa17 mRNA","pmids":["18492746"],"confidence":"Medium","gaps":["Functional effect of RBMY binding on SPA17 translation/stability unestablished","Single-lab EMSA without in vivo regulatory validation"]},{"year":2018,"claim":"Defined SPA17 as a surface-exposed protein with a discrete C-terminal calmodulin-binding domain via its proteolytic susceptibility.","evidence":"α-chymotrypsin treatment of human sperm with Western blot detection of a 17 kDa cleavage product","pmids":["29409138"],"confidence":"Low","gaps":["Single biochemical assay inferring domain identity from cleavage size","Direct calmodulin binding not demonstrated functionally"]},{"year":2021,"claim":"Resolved the structural basis of SPA17 function, showing its D/D domain oligomerizes and that high-affinity AKAP18 docking requires heterodimerization with ropporin-1-like protein.","evidence":"1.72 Å X-ray crystal structure of the D/D domain plus solution oligomerization and quantitative binding assays","pmids":["34256050"],"confidence":"High","gaps":["Structure limited to residues 1-75; C-terminal calmodulin-binding region not resolved","In vivo relevance of homotetramer versus heterodimer states not established"]},{"year":2021,"claim":"Connected SPA17 to redox signaling by demonstrating it is directly modified by reversible cysteine oxidation during capacitation.","evidence":"Fluorescent gel-based redox proteomics, Western blot and flow cytometry on bull sperm across capacitation","pmids":["34360666"],"confidence":"Medium","gaps":["Specific oxidized cysteines not mapped","Functional consequence of oxidation for scaffold or PKA activity not tested"]},{"year":2022,"claim":"Showed SPA17 is an active PKA-pathway substrate, identifying capacitation-induced Y156 phosphorylation.","evidence":"Quantitative TMT phosphoproteomics (LC-MS/MS) across yak sperm capacitation states","pmids":["36277216"],"confidence":"Medium","gaps":["Responsible kinase not directly identified","Functional output of Y156 phosphorylation untested"]},{"year":2023,"claim":"Placed SPA17 within the AKAP4/PKA capacitation axis at the clinical level, linking its dysregulation to oxidative stress and impaired sperm function.","evidence":"Western blot of H-DFI patient sperm, H2O2 oxidative-stress model, and IVF outcome correlation","pmids":["37695244"],"confidence":"Medium","gaps":["Correlative expression changes do not establish causation","Mechanism linking SPA17 increase to capacitation failure unresolved"]},{"year":null,"claim":"How SPA17's oligomerization state, phosphorylation, oxidation, and calmodulin binding are integrated to regulate PKA-dependent capacitation and motility remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No reconstitution linking PTMs to AKAP18/AKAP4 docking dynamics","No loss-of-function motility phenotype for SPA17 itself","Olfactory ciliary function uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[6]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[1,4]}],"complexes":["fibrous sheath"],"partners":["AKAP18","ROPN1L","AKAP4","RBMY"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15506","full_name":"Sperm surface protein Sp17","aliases":["Cancer/testis antigen 22","CT22","Sp17-1","Sperm autoantigenic protein 17","Sperm protein 17"],"length_aa":151,"mass_kda":17.4,"function":"Sperm surface zona pellucida binding protein. Helps to bind spermatozoa to the zona pellucida with high affinity. Might function in binding zona pellucida and carbohydrates (By similarity)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q15506/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SPA17","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SPA17","total_profiled":1310},"omim":[{"mim_id":"611757","title":"RHOPHILIN-ASSOCIATED TAIL PROTEIN 1; ROPN1","url":"https://www.omim.org/entry/611757"},{"mim_id":"611756","title":"RHOPHILIN ASSOCIATED TAIL PROTEIN 1-LIKE; ROPN1L","url":"https://www.omim.org/entry/611756"},{"mim_id":"608621","title":"SPERM AUTOANTIGENIC PROTEIN 17; SPA17","url":"https://www.omim.org/entry/608621"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Principal piece","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"fallopian tube","ntpm":23.1},{"tissue":"testis","ntpm":36.7}],"url":"https://www.proteinatlas.org/search/SPA17"},"hgnc":{"alias_symbol":["SP17","CT22"],"prev_symbol":[]},"alphafold":{"accession":"Q15506","domains":[{"cath_id":"-","chopping":"15-71","consensus_level":"high","plddt":91.0896,"start":15,"end":71},{"cath_id":"1.20.5","chopping":"107-151","consensus_level":"medium","plddt":84.9976,"start":107,"end":151}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15506","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15506-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15506-F1-predicted_aligned_error_v6.png","plddt_mean":77.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SPA17","jax_strain_url":"https://www.jax.org/strain/search?query=SPA17"},"sequence":{"accession":"Q15506","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15506.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15506/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15506"}},"corpus_meta":[{"pmid":"9428527","id":"PMC_9428527","title":"A 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production","url":"https://pubmed.ncbi.nlm.nih.gov/40711514","citation_count":1,"is_preprint":false},{"pmid":"41892387","id":"PMC_41892387","title":"Deletion of Clock Gene Period1 (Per1) in Neurons but Not in Astrocytes Shortens Clock Period and Diminishes Light-Mediated Rapid Phase Advances in Mice.","date":"2026","source":"Clocks & sleep","url":"https://pubmed.ncbi.nlm.nih.gov/41892387","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":25350,"output_tokens":1896,"usd":0.052245,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8836,"output_tokens":2738,"usd":0.056315,"stage2_stop_reason":"end_turn"},"total_usd":0.10856,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structure of the SPA17 D/D domain (amino acids 1-75) resolved at 1.72 Å reveals a four-helix bundle-like configuration with terminal β-strands that mediate higher-order oligomerization. In solution, SPA17 forms both homodimers and tetramers and displays weak affinity for AKAP18 alone, but binds AKAP18 at nanomolar affinity when SPA17 heterodimerizes with the ropporin-1-like D/D protein.\",\n      \"method\": \"X-ray crystallography (1.72 Å), solution biophysics (oligomerization assays), quantitative binding affinity measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional validation (heterodimerization and AKAP18 binding quantified), single lab but multiple orthogonal methods\",\n      \"pmids\": [\"34256050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In Akap4 knockout mice, the fibrous sheath is disrupted and the subcellular distribution of SP17 (SPA17) is altered, demonstrating that SPA17 localization in the sperm flagellum depends on AKAP4-mediated fibrous sheath integrity.\",\n      \"method\": \"Akap4 gene knockout mouse model with immunofluorescence/subcellular fractionation to assess SP17 distribution\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean genetic KO with defined localization phenotype, single lab, single method reported in abstract\",\n      \"pmids\": [\"15385410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In yak sperm, phosphorylation of SPA17 at Y156 increases during capacitation, identifying SPA17 as a phosphorylation substrate regulated through the cAMP/PKA signaling pathway and suggesting a functional role in sperm capacitation beyond scaffold AKAPs.\",\n      \"method\": \"Quantitative phosphoproteomics (TMT labeling + LC-MS/MS) across sperm capacitation states\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — site-specific phosphorylation identified by mass spectrometry in a relevant biological context, single lab, single method\",\n      \"pmids\": [\"36277216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"During bull sperm capacitation, SPA17 undergoes reversible oxidative post-translational modifications (oxPTMs) at susceptible cysteines, linking SPA17 to redox-regulated cAMP/PKA pathway signaling during capacitation.\",\n      \"method\": \"Fluorescent gel-based redox proteomics, Western blot, flow cytometry\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct detection of oxPTMs on SPA17 using redox proteomics, single lab, moderate methodological depth\",\n      \"pmids\": [\"34360666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In high sperm DNA fragmentation index (H-DFI) patients, SPA17 protein expression is increased while AKAP4 and PKARII are decreased; H2O2-induced oxidative stress mimics this pattern and inhibits sperm capacitation and acrosome reaction, placing SPA17 within the AKAP4/PKA signaling axis that regulates capacitation.\",\n      \"method\": \"Western blot on patient sperm samples; H2O2 oxidative stress model in sperm; IVF outcome correlation\",\n      \"journal\": \"Asian journal of andrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional pathway placement via protein expression changes and oxidative stress model, single lab, two orthogonal approaches (patient samples + H2O2 model)\",\n      \"pmids\": [\"37695244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Mouse RBMY protein binds to spa17 mRNA from testis; electrophoretic mobility shift assay demonstrated direct binding, with the binding domain containing rich oligo(A) sequences, suggesting mRBMY has high affinity for oligo(A)-rich sequences including spa17 mRNA.\",\n      \"method\": \"Immunoprecipitation of RNA-protein complexes from testis, electrophoretic mobility shift assay (EMSA)\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct RNA-protein binding demonstrated by EMSA with domain characterization, single lab\",\n      \"pmids\": [\"18492746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SPA17 protein colocalizes with acetylated tubulin in the cilia layer of mouse olfactory epithelium, establishing SPA17 as a component of sensory cilia in olfactory sensory neurons.\",\n      \"method\": \"Immunofluorescence colocalization with acetylated tubulin in olfactory epithelium sections\",\n      \"journal\": \"Physiological genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — direct immunolocalization in tissue, single lab, single method, no functional consequence tested\",\n      \"pmids\": [\"17971504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Treatment of human sperm with α-chymotrypsin degrades SPA17 from the sperm surface, generating a 17 kDa cleavage product (loss of C-terminal calmodulin-binding domain) from the native 20 kDa form, demonstrating that SPA17 is a surface-exposed protein with a C-terminal calmodulin-binding domain susceptible to proteolytic cleavage.\",\n      \"method\": \"Western blot analysis of α-chymotrypsin-treated sperm samples\",\n      \"journal\": \"Andrology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single biochemical experiment revealing domain structure via proteolysis, single lab, single method\",\n      \"pmids\": [\"29409138\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SPA17 (sperm autoantigenic protein 17) is a sperm- and cilia-expressed protein whose D/D domain forms homodimers and tetramers and heterodimerizes with ropporin-1-like protein to bind AKAP18 at nanomolar affinity, placing it within the AKAP/PKA signaling scaffold of the sperm flagellum; its localization to the fibrous sheath depends on AKAP4 integrity, its Y156 residue is phosphorylated during capacitation via the cAMP/PKA pathway, and it undergoes redox-regulated oxPTMs during capacitation, collectively indicating that SPA17 functions as a structural and signaling scaffold protein coordinating PKA-mediated regulation of sperm capacitation and motility.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SPA17 (sperm autoantigenic protein 17) is a sperm- and cilia-associated scaffold protein that integrates into the AKAP/PKA signaling architecture of the sperm flagellum and coordinates redox- and phosphorylation-regulated events during capacitation [#0, #4]. Its N-terminal dimerization/docking (D/D) domain (residues 1-75) folds into a four-helix-bundle-like configuration whose terminal β-strands drive higher-order oligomerization; SPA17 forms homodimers and tetramers in solution and binds AKAP18 with nanomolar affinity only upon heterodimerization with the ropporin-1-like D/D protein, placing it as an AKAP-docking module rather than a free monomer [#0]. Proper flagellar localization of SPA17 to the fibrous sheath depends on AKAP4 integrity, as Akap4 knockout disrupts the fibrous sheath and alters SPA17 distribution [#1]. During capacitation SPA17 is a regulated target of cAMP/PKA signaling: it is phosphorylated at Y156 [#2] and undergoes reversible oxidative modifications at susceptible cysteines [#3], and in high-DNA-fragmentation sperm its expression rises while AKAP4 and PKARII fall, mirroring an oxidative-stress phenotype that impairs capacitation and the acrosome reaction [#4]. SPA17 also localizes to sensory cilia of olfactory neurons, indicating a broader ciliary role beyond sperm [#6]. The protein is surface-exposed and carries a protease-susceptible C-terminal calmodulin-binding domain [#7], and its testicular mRNA is bound directly by the RNA-binding protein RBMY [#5].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that SPA17's flagellar positioning is not autonomous but depends on a defined structural scaffold, linking it to fibrous sheath architecture.\",\n      \"evidence\": \"Akap4 knockout mouse with immunolocalization/fractionation of SP17\",\n      \"pmids\": [\"15385410\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not show direct AKAP4-SPA17 binding versus indirect dependence on sheath integrity\", \"Functional consequence of mislocalization for motility not measured\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended SPA17 beyond sperm by placing it in sensory cilia, implying a conserved ciliary function.\",\n      \"evidence\": \"Immunofluorescence colocalization with acetylated tubulin in mouse olfactory epithelium\",\n      \"pmids\": [\"17971504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional role in olfactory signaling tested\", \"Mechanism of ciliary targeting unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified a post-transcriptional control point by showing SPA17 mRNA is a direct binding target of an RNA-binding protein in testis.\",\n      \"evidence\": \"RNP immunoprecipitation and EMSA from testis demonstrating RBMY binding to oligo(A)-rich spa17 mRNA\",\n      \"pmids\": [\"18492746\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional effect of RBMY binding on SPA17 translation/stability unestablished\", \"Single-lab EMSA without in vivo regulatory validation\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined SPA17 as a surface-exposed protein with a discrete C-terminal calmodulin-binding domain via its proteolytic susceptibility.\",\n      \"evidence\": \"α-chymotrypsin treatment of human sperm with Western blot detection of a 17 kDa cleavage product\",\n      \"pmids\": [\"29409138\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single biochemical assay inferring domain identity from cleavage size\", \"Direct calmodulin binding not demonstrated functionally\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the structural basis of SPA17 function, showing its D/D domain oligomerizes and that high-affinity AKAP18 docking requires heterodimerization with ropporin-1-like protein.\",\n      \"evidence\": \"1.72 Å X-ray crystal structure of the D/D domain plus solution oligomerization and quantitative binding assays\",\n      \"pmids\": [\"34256050\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure limited to residues 1-75; C-terminal calmodulin-binding region not resolved\", \"In vivo relevance of homotetramer versus heterodimer states not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected SPA17 to redox signaling by demonstrating it is directly modified by reversible cysteine oxidation during capacitation.\",\n      \"evidence\": \"Fluorescent gel-based redox proteomics, Western blot and flow cytometry on bull sperm across capacitation\",\n      \"pmids\": [\"34360666\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific oxidized cysteines not mapped\", \"Functional consequence of oxidation for scaffold or PKA activity not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed SPA17 is an active PKA-pathway substrate, identifying capacitation-induced Y156 phosphorylation.\",\n      \"evidence\": \"Quantitative TMT phosphoproteomics (LC-MS/MS) across yak sperm capacitation states\",\n      \"pmids\": [\"36277216\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Responsible kinase not directly identified\", \"Functional output of Y156 phosphorylation untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed SPA17 within the AKAP4/PKA capacitation axis at the clinical level, linking its dysregulation to oxidative stress and impaired sperm function.\",\n      \"evidence\": \"Western blot of H-DFI patient sperm, H2O2 oxidative-stress model, and IVF outcome correlation\",\n      \"pmids\": [\"37695244\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative expression changes do not establish causation\", \"Mechanism linking SPA17 increase to capacitation failure unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SPA17's oligomerization state, phosphorylation, oxidation, and calmodulin binding are integrated to regulate PKA-dependent capacitation and motility remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstitution linking PTMs to AKAP18/AKAP4 docking dynamics\", \"No loss-of-function motility phenotype for SPA17 itself\", \"Olfactory ciliary function uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"complexes\": [\"fibrous sheath\"],\n    \"partners\": [\"AKAP18\", \"ROPN1L\", \"AKAP4\", \"RBMY\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}