{"gene":"CRISP1","run_date":"2026-04-28T17:28:53","timeline":{"discoveries":[{"year":1996,"finding":"Human CRISP1 is epididymis-specific at the mRNA level; the protein contains 16 conserved cysteine residues forming a modular structure with an N-terminal PR-like domain and a C-terminal cysteine-rich domain (CRD); all 16 cysteines are engaged in disulfide bonds, with the six N-terminal cysteines forming three intra-domain bonds, suggesting two discrete structural domains.","method":"cDNA cloning, Northern blot, N-terminal sequencing, ethyl maleimide treatment, proteolytic digestion of recombinant protein","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 — biochemical characterization of disulfide bond pattern in recombinant protein with multiple orthogonal methods","pmids":["8665901","8562061"],"is_preprint":false},{"year":2003,"finding":"Rat CRISP1 (Protein DE) associates with the sperm surface in the epididymis and is lost during in vitro capacitation; exogenous CRISP1 inhibits capacitation-associated protein tyrosine phosphorylation in a dose-dependent manner, placing its decapacitating action upstream of cAMP production, and consequently inhibits the acrosome reaction.","method":"In vitro sperm capacitation assay, Western blot, exogenous protein addition, dose-response inhibition of tyrosine phosphorylation","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 — clean functional assay with dose-response and upstream pathway placement, replicated across labs","pmids":["12700197"],"is_preprint":false},{"year":2001,"finding":"Human CRISP1 (ARP) is tightly associated with the surface of ejaculated sperm and mediates gamete fusion; antibodies against ARP inhibit penetration of zona-free hamster eggs without affecting sperm viability, motility, or acrosome reaction; complementary ARP-binding sites were identified on the surface of human eggs by indirect immunofluorescence.","method":"Sequential protein extraction, polyclonal antibody inhibition assay, zona-free egg penetration assay, indirect immunofluorescence of egg surface binding","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (antibody inhibition + egg surface binding), consistent with rodent data from other labs","pmids":["11566719"],"is_preprint":false},{"year":2007,"finding":"CRISP1 participates in the initial step of sperm binding to the zona pellucida (ZP) in addition to gamete fusion; native CRISP1 binds directly to the ZP in a conformation-dependent (not glycan-dependent) manner that mimics sperm-ZP binding behavior; recombinant CRISP1 binds only to the oolema, not the ZP.","method":"In vitro fertilization inhibition assays (rat and mouse), anti-CRISP1 antibody, indirect immunofluorescence of protein binding to ZP and oolema, heat denaturation and deglycosylation controls","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 — multiple complementary functional and binding assays with rigorous controls","pmids":["17671267"],"is_preprint":false},{"year":2008,"finding":"Crisp1 knockout mice produce sperm with reduced protein tyrosine phosphorylation during capacitation and significantly impaired ability to penetrate both ZP-intact and ZP-free eggs in vitro; in competition assays Crisp1-/- sperm show greater disadvantage in fusion ability, and residual fusion is further inhibited by exogenous CRISP1 or CRISP2, suggesting functional redundancy with another CRISP family member.","method":"Gene knockout (Crisp1-/- mice), in vitro fertilization assays, sperm tyrosine phosphorylation by Western blot, competition insemination assay, acrosome reaction assay","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — rigorous KO with multiple orthogonal phenotypic readouts and competition controls","pmids":["18571638"],"is_preprint":false},{"year":2004,"finding":"Bicarbonate is required for CRISP1 (DE) migration from the dorsal region of the sperm head to the equatorial segment during capacitation, and sperm capacitated without bicarbonate—even if the anion is restored during gamete co-incubation—cannot fuse with eggs; cAMP analogs restore tyrosine phosphorylation but not DE migration, indicating a cAMP-independent bicarbonate requirement for CRISP1 redistribution.","method":"Sperm capacitation under defined ionic conditions, immunofluorescence tracking of DE localization, tyrosine phosphorylation Western blot, cAMP analog rescue experiments, egg penetration assay","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 — systematic dissection with multiple conditions and orthogonal readouts","pmids":["14711787"],"is_preprint":false},{"year":2006,"finding":"The D and E isoforms of rat CRISP1 differ by an O-linked N-acetylgalactosamine on a threonine near the N-terminus of protein E; protein D associates transiently with sperm in a saturable, concentration-dependent manner consistent with its capacitation-inhibiting activity, while protein E becomes stably incorporated into sperm surface in the cauda epididymis and persists through capacitation.","method":"Tandem MS/MS, monosaccharide composition analysis, in vitro sperm-binding assays, Western blot, monoclonal antibody epitope characterization","journal":"Molecular and cellular endocrinology / Biology of reproduction","confidence":"High","confidence_rationale":"Tier 1-2 — mass spectrometry-based PTM identification combined with functional binding assays","pmids":["16414181","18703418"],"is_preprint":false},{"year":2011,"finding":"Zn2+ promotes association of the loosely bound population of CRISP1 with sperm by forming high-molecular-weight CRISP1-Zn2+ complexes; Zn2+ directly interacts with CRISP1 as evidenced by changes in tryptophan fluorescence emission spectra; EDTA prevents complex formation and sperm binding.","method":"In vitro sperm incubation with purified CRISP1 ± Zn2+/EDTA, Western blot, flow cytometry, epifluorescence microscopy, tryptophan fluorescence spectroscopy, native-PAGE","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 1-2 — direct biophysical evidence of CRISP1-Zn2+ interaction combined with functional sperm-binding assay","pmids":["21593480"],"is_preprint":false},{"year":2015,"finding":"CRISP1 is expressed by cumulus cells surrounding the egg and regulates sperm hyperactivation and orientation required for cumulus penetration; patch-clamp recordings show CRISP1 can directly modulate CatSper, the principal sperm Ca2+ channel involved in hyperactivation; Crisp1 KO females show impaired fertilization of cumulus-oocyte complexes due to sperm failure to penetrate the cumulus.","method":"Crisp1 KO females, fertilization assays with cumulus-oocyte complexes, sperm hyperactivation analysis, patch-clamp electrophysiology of sperm CatSper channel","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — direct electrophysiological measurement of channel modulation plus KO functional assay","pmids":["26416967"],"is_preprint":false},{"year":2018,"finding":"Crisp1-/- sperm on a homogeneous C57BL/6 background exhibit defects in progesterone-induced acrosome reaction, motility, and hyperactivation, as well as reduced cAMP and PKA substrate phosphorylation; treatment with a cAMP analog and phosphodiesterase inhibitor rescues these defects, placing CRISP1 upstream of the cAMP-PKA signaling pathway in capacitation.","method":"Backcrossed Crisp1-/- mice, acrosome reaction assay, sperm motility/hyperactivation analysis, cAMP measurement, PKA substrate phosphorylation Western blot, pharmacological rescue with cAMP analogs","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with pharmacological rescue precisely placing CRISP1 in cAMP-PKA pathway","pmids":["29481619"],"is_preprint":false},{"year":2021,"finding":"Zn2+ induces oligomerization of human CRISP1 via the conserved His142 residue in the CAP domain; removal of Zn2+ by EDTA dissociates oligomers back to monomers; the isolated CAP domain alone undergoes the same Zn2+-dependent oligomerization, demonstrating that the CAP metal-binding site mediates this interaction.","method":"Recombinant MBP-tagged CRISP1 expression, in vitro Zn2+ addition, size-exclusion analysis, EDTA dissociation, His142 site-directed mutagenesis","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with active-site mutagenesis demonstrating mechanism","pmids":["33750840"],"is_preprint":false},{"year":2003,"finding":"Microinjection of DE (CRISP1) into eggs does not trigger Ca2+ oscillations or meiosis resumption, and does not modify oscillations induced by a sperm extract, arguing against a role for CRISP1 as a sperm-borne egg activation factor; its activity is restricted to the sperm-egg fusion step via interaction with egg surface binding sites.","method":"Egg incubation with DE protein, intracellular Ca2+ imaging, microinjection, meiosis resumption assay","journal":"Cellular and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional test ruling out egg activation role; single lab, single study","pmids":["12887093"],"is_preprint":false},{"year":2024,"finding":"PD-L1 overexpression in mouse testis causes overexpression of CRISP1 in the epididymis; PD-L1 and CRISP1 can interact with each other; this leads to impaired sperm-zona pellucida binding and sperm-oocyte fusion, resulting in male infertility.","method":"Transgenic PD-L1 overexpression mouse model, CRISP1 protein expression analysis, sperm functional assays","journal":"Zygote","confidence":"Low","confidence_rationale":"Tier 3 — single lab, interaction evidence not rigorously characterized, limited mechanistic detail","pmids":["38828560"],"is_preprint":false}],"current_model":"CRISP1 is an epididymally secreted, modular cysteine-rich protein that associates with sperm during maturation in two populations (loosely and tightly bound, distinguished by glycosylation state and zinc-dependent oligomerization); it acts as a decapacitation factor by inhibiting capacitation-associated tyrosine phosphorylation and cAMP-PKA signaling, redistributes to the equatorial segment upon capacitation in a bicarbonate-dependent manner, and subsequently participates in both sperm-zona pellucida binding and gamete fusion through interaction with complementary egg-surface sites; additionally, cumulus-cell-expressed CRISP1 modulates the sperm CatSper Ca2+ channel to regulate hyperactivation and sperm orientation during fertilization."},"narrative":{"teleology":[{"year":1996,"claim":"Establishing the modular architecture of CRISP1 — the two-domain structure (PR-like/CAP + CRD) with all 16 cysteines engaged in disulfide bonds — provided the structural framework for understanding how distinct protein regions mediate different functions.","evidence":"cDNA cloning, Northern blot, proteolytic digestion and ethyl maleimide treatment of recombinant human CRISP1","pmids":["8665901","8562061"],"confidence":"High","gaps":["No crystal or cryo-EM structure solved","Functional contribution of individual disulfide bonds not tested","CRD versus CAP domain function not yet dissected"]},{"year":2001,"claim":"Demonstrating that CRISP1 on ejaculated sperm mediates gamete fusion via egg-surface binding sites established its direct fertilization role beyond epididymal coating.","evidence":"Polyclonal antibody inhibition of zona-free hamster egg penetration by human sperm; immunofluorescence of egg-surface CRISP1-binding sites","pmids":["11566719"],"confidence":"High","gaps":["Identity of the egg-surface receptor unknown","Whether fusion role is conserved across species not systematically tested"]},{"year":2003,"claim":"Showing that exogenous CRISP1 inhibits capacitation-associated tyrosine phosphorylation upstream of cAMP production defined it as a decapacitation factor and placed its inhibitory action at the top of the signaling cascade.","evidence":"Dose-response inhibition of tyrosine phosphorylation during rat sperm in vitro capacitation","pmids":["12700197"],"confidence":"High","gaps":["Direct molecular target mediating decapacitation not identified","Mechanism by which CRISP1 suppresses cAMP production unknown"]},{"year":2004,"claim":"Revealing that CRISP1 redistribution from the dorsal head to the equatorial segment requires bicarbonate through a cAMP-independent pathway linked protein relocalization to fusion competence.","evidence":"Immunofluorescence tracking of CRISP1 localization under defined ionic conditions with cAMP analog rescue; rat sperm egg-penetration assay","pmids":["14711787"],"confidence":"High","gaps":["Molecular mechanism of bicarbonate-driven redistribution unknown","Whether membrane lipid remodeling drives CRISP1 migration not tested"]},{"year":2006,"claim":"Identifying that a single O-GalNAc distinguishes the loosely bound (decapacitating) from the tightly bound (fusion-competent) CRISP1 population explained how one gene product fulfills two opposing roles on sperm.","evidence":"Tandem MS/MS glycosylation mapping; in vitro sperm binding assays comparing D and E isoforms","pmids":["16414181","18703418"],"confidence":"High","gaps":["Enzyme responsible for O-GalNAc addition not identified","Whether human CRISP1 has analogous glycoform populations not confirmed"]},{"year":2007,"claim":"Extending CRISP1's fertilization role to zona pellucida binding — in a conformation-dependent, glycan-independent manner — showed the protein participates in both primary gamete recognition and fusion.","evidence":"Native versus recombinant CRISP1 binding to ZP and oolema; IVF inhibition assays in rat and mouse","pmids":["17671267"],"confidence":"High","gaps":["Which ZP glycoprotein CRISP1 binds not determined","Structural basis for conformation-dependent ZP binding unknown"]},{"year":2008,"claim":"Crisp1 knockout confirmed the protein's in vivo necessity for efficient fertilization and revealed functional redundancy with CRISP2 at the fusion step.","evidence":"Crisp1−/− mice; in vitro fertilization with ZP-intact and ZP-free eggs; competition insemination; exogenous CRISP1/CRISP2 inhibition","pmids":["18571638"],"confidence":"High","gaps":["Extent of CRISP1–CRISP2 redundancy in vivo not fully resolved","Whether Crisp1/Crisp2 double KO is infertile not tested"]},{"year":2011,"claim":"Demonstrating Zn²⁺-dependent oligomerization of CRISP1 and its role in promoting sperm association provided a biophysical mechanism for how epididymal zinc concentrations regulate decapacitation factor loading.","evidence":"In vitro Zn²⁺ incubation, tryptophan fluorescence spectroscopy, native-PAGE, EDTA dissociation, flow cytometry of sperm-bound CRISP1","pmids":["21593480"],"confidence":"High","gaps":["Stoichiometry and structure of CRISP1-Zn²⁺ oligomers not resolved","In vivo zinc dynamics during epididymal transit not measured"]},{"year":2015,"claim":"Discovering cumulus-cell-expressed CRISP1 and its direct modulation of the CatSper Ca²⁺ channel expanded CRISP1's role from a sperm-intrinsic factor to an oviductal guidance cue regulating hyperactivation.","evidence":"Crisp1 KO female fertilization assays with cumulus-oocyte complexes; patch-clamp electrophysiology of sperm CatSper","pmids":["26416967"],"confidence":"High","gaps":["Whether CRISP1 activates or inhibits CatSper in physiological context not fully clarified","Binding site on CatSper complex not mapped"]},{"year":2018,"claim":"Pharmacological rescue of Crisp1−/− sperm with cAMP analogs precisely placed CRISP1 upstream of the cAMP-PKA cascade, confirming the pathway hierarchy suggested by earlier biochemical studies.","evidence":"Backcrossed Crisp1−/− mice on C57BL/6; cAMP measurement, PKA substrate phosphorylation, pharmacological rescue of acrosome reaction and hyperactivation","pmids":["29481619"],"confidence":"High","gaps":["Direct molecular target through which CRISP1 promotes cAMP production still unknown","Whether CRISP1 regulates adenylyl cyclase or phosphodiesterase not distinguished"]},{"year":2021,"claim":"Mapping the Zn²⁺-dependent oligomerization to the conserved His142 in the CAP domain provided the first residue-level mechanistic insight into CRISP1 self-association.","evidence":"Recombinant CAP domain expression, site-directed mutagenesis of His142, size-exclusion chromatography, EDTA reversibility","pmids":["33750840"],"confidence":"High","gaps":["Full atomic structure of Zn²⁺-bound oligomer not determined","Whether His142 mutation affects sperm binding or fertilization in vivo not tested"]},{"year":null,"claim":"Key unresolved questions include the identity of the egg-surface CRISP1 receptor, the direct molecular target linking CRISP1 to cAMP production during capacitation, and the structural basis for conformation-dependent zona pellucida recognition.","evidence":"","pmids":[],"confidence":"High","gaps":["Egg-surface CRISP1 receptor unidentified","Mechanism connecting CRISP1 to adenylyl cyclase or phosphodiesterase activity unknown","No high-resolution structure of CRISP1 or CRISP1-Zn²⁺ oligomer available","CRISP1/CRISP2 double knockout fertility phenotype not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,8,9]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[2,3,8]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,6,7,8]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[2,3,4,5,8,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,9]}],"complexes":[],"partners":["CATSPER1","CRISP2"],"other_free_text":[]},"mechanistic_narrative":"CRISP1 is an epididymally secreted, cysteine-rich secretory protein that functions at multiple steps of mammalian fertilization — from sperm capacitation to zona pellucida binding and gamete fusion. The protein associates with sperm in two populations distinguished by glycosylation and zinc-dependent oligomerization via the CAP domain His142 residue: a loosely bound, Zn²⁺-stabilized population that acts as a decapacitation factor by inhibiting cAMP-PKA signaling and tyrosine phosphorylation, and a tightly bound population that redistributes to the equatorial segment in a bicarbonate-dependent manner during capacitation to mediate sperm–zona pellucida binding and sperm–egg fusion through interaction with complementary egg-surface sites [PMID:12700197, PMID:16414181, PMID:33750840, PMID:14711787, PMID:11566719, PMID:17671267]. Crisp1 knockout sperm exhibit defective cAMP-PKA signaling, reduced hyperactivation, and impaired fertilization both at the zona and oolemma, with cAMP analog rescue confirming CRISP1 acts upstream of PKA [PMID:18571638, PMID:29481619]. Cumulus-cell-expressed CRISP1 additionally modulates the sperm CatSper Ca²⁺ channel to regulate hyperactivation required for cumulus penetration [PMID:26416967]."},"prefetch_data":{"uniprot":{"accession":"P54107","full_name":"Cysteine-rich secretory protein 1","aliases":["AEG-like protein","ARP","Acidic epididymal glycoprotein homolog"],"length_aa":249,"mass_kda":28.5,"function":"May have a role in sperm-egg fusion and maturation","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P54107/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CRISP1","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CRISP1","total_profiled":1310},"omim":[{"mim_id":"618062","title":"CYSTEINE-RICH SECRETORY PROTEIN 3; CRISP3","url":"https://www.omim.org/entry/618062"},{"mim_id":"601193","title":"CYSTEINE-RICH SECRETORY PROTEIN 1; CRISP1","url":"https://www.omim.org/entry/601193"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"epididymis","ntpm":1486.0}],"url":"https://www.proteinatlas.org/search/CRISP1"},"hgnc":{"alias_symbol":["CRISP-1","ARP","HUMARP","HSCRISP1D","HSCRISP1G"],"prev_symbol":["AEGL1"]},"alphafold":{"accession":"P54107","domains":[{"cath_id":"3.40.33.10","chopping":"32-210","consensus_level":"high","plddt":95.9862,"start":32,"end":210},{"cath_id":"1.10.10.740","chopping":"211-249","consensus_level":"medium","plddt":95.0882,"start":211,"end":249}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P54107","model_url":"https://alphafold.ebi.ac.uk/files/AF-P54107-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P54107-F1-predicted_aligned_error_v6.png","plddt_mean":93.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CRISP1","jax_strain_url":"https://www.jax.org/strain/search?query=CRISP1"},"sequence":{"accession":"P54107","fasta_url":"https://rest.uniprot.org/uniprotkb/P54107.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P54107/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P54107"}},"corpus_meta":[{"pmid":"18600222","id":"PMC_18600222","title":"Automated macromolecular model building for X-ray crystallography using ARP/wARP version 7.","date":"2008","source":"Nature protocols","url":"https://pubmed.ncbi.nlm.nih.gov/18600222","citation_count":1421,"is_preprint":false},{"pmid":"11567158","id":"PMC_11567158","title":"ARP/wARP and molecular replacement.","date":"2001","source":"Acta crystallographica. Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/11567158","citation_count":469,"is_preprint":false},{"pmid":"1899293","id":"PMC_1899293","title":"Regulation of the apolipoprotein AI gene by ARP-1, a novel member of the steroid receptor superfamily.","date":"1991","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/1899293","citation_count":389,"is_preprint":false},{"pmid":"1639815","id":"PMC_1639815","title":"Transcriptional regulation of human apolipoprotein genes ApoB, ApoCIII, and ApoAII by members of the steroid hormone receptor superfamily HNF-4, ARP-1, EAR-2, and EAR-3.","date":"1992","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1639815","citation_count":285,"is_preprint":false},{"pmid":"7878030","id":"PMC_7878030","title":"The p150Glued component of the dynactin complex binds to both microtubules and the actin-related protein centractin (Arp-1).","date":"1995","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7878030","citation_count":272,"is_preprint":false},{"pmid":"12429613","id":"PMC_12429613","title":"Arf, Arl, Arp and Sar proteins: a family of GTP-binding proteins with a structural device for 'front-back' communication.","date":"2002","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/12429613","citation_count":251,"is_preprint":false},{"pmid":"8665901","id":"PMC_8665901","title":"The human cysteine-rich secretory protein (CRISP) family. Primary structure and tissue distribution of CRISP-1, CRISP-2 and CRISP-3.","date":"1996","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8665901","citation_count":182,"is_preprint":false},{"pmid":"7823919","id":"PMC_7823919","title":"A dynamic balance between ARP-1/COUP-TFII, EAR-3/COUP-TFI, and retinoic acid receptor:retinoid X receptor heterodimers regulates Oct-3/4 expression in embryonal carcinoma cells.","date":"1995","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7823919","citation_count":138,"is_preprint":false},{"pmid":"10511705","id":"PMC_10511705","title":"The world according to Arp: regulation of actin nucleation by the Arp2/3 complex.","date":"1999","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10511705","citation_count":135,"is_preprint":false},{"pmid":"1321332","id":"PMC_1321332","title":"Repression by ARP-1 sensitizes apolipoprotein AI gene responsiveness to RXR alpha and retinoic acid.","date":"1992","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/1321332","citation_count":133,"is_preprint":false},{"pmid":"14646134","id":"PMC_14646134","title":"Breaking good resolutions with ARP/wARP.","date":"2003","source":"Journal of synchrotron radiation","url":"https://pubmed.ncbi.nlm.nih.gov/14646134","citation_count":130,"is_preprint":false},{"pmid":"12700197","id":"PMC_12700197","title":"Inhibition of capacitation-associated tyrosine phosphorylation signaling in rat sperm by epididymal protein Crisp-1.","date":"2003","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/12700197","citation_count":123,"is_preprint":false},{"pmid":"8288643","id":"PMC_8288643","title":"The directly repeated RG(G/T)TCA motifs of the rat and mouse cellular retinol-binding protein II genes are promiscuous binding sites for RAR, RXR, HNF-4, and ARP-1 homo- and heterodimers.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8288643","citation_count":120,"is_preprint":false},{"pmid":"18571638","id":"PMC_18571638","title":"Impaired sperm fertilizing ability in mice lacking Cysteine-RIch Secretory Protein 1 (CRISP1).","date":"2008","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/18571638","citation_count":119,"is_preprint":false},{"pmid":"9726966","id":"PMC_9726966","title":"Subunits of the yeast SWI/SNF complex are members of the actin-related protein (ARP) family.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9726966","citation_count":116,"is_preprint":false},{"pmid":"8319566","id":"PMC_8319566","title":"Transcripts for cysteine-rich secretory protein-1 (CRISP-1; DE/AEG) and the novel related CRISP-3 are expressed under androgen control in the mouse salivary gland.","date":"1993","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/8319566","citation_count":110,"is_preprint":false},{"pmid":"8562061","id":"PMC_8562061","title":"Mouse androgen-dependent epididymal glycoprotein CRISP-1 (DE/AEG): isolation, biochemical characterization, and expression in recombinant form.","date":"1995","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/8562061","citation_count":89,"is_preprint":false},{"pmid":"11722735","id":"PMC_11722735","title":"Efficient uptake of Yersinia pseudotuberculosis via integrin receptors involves a Rac1-Arp 2/3 pathway that bypasses N-WASP function.","date":"2001","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/11722735","citation_count":84,"is_preprint":false},{"pmid":"11566719","id":"PMC_11566719","title":"Evidence that human epididymal protein ARP plays a role in gamete fusion through complementary sites on the surface of the human egg.","date":"2001","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/11566719","citation_count":82,"is_preprint":false},{"pmid":"9580705","id":"PMC_9580705","title":"Multiple parameters determine the specificity of transcriptional response by nuclear receptors HNF-4, ARP-1, PPAR, RAR and RXR through common response elements.","date":"1998","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/9580705","citation_count":81,"is_preprint":false},{"pmid":"8027069","id":"PMC_8027069","title":"Interaction of the peroxisome proliferator-activated receptor alpha with the retinoid X receptor alpha unmasks a cryptic peroxisome proliferator response element that overlaps an ARP-1-binding site in the CYP4A6 promoter.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8027069","citation_count":81,"is_preprint":false},{"pmid":"26416967","id":"PMC_26416967","title":"CRISP1 as a novel CatSper regulator that modulates sperm motility and orientation during fertilization.","date":"2015","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/26416967","citation_count":73,"is_preprint":false},{"pmid":"7806375","id":"PMC_7806375","title":"Expression of the Arp protein, a member of the M protein family, is not sufficient to inhibit phagocytosis of Streptococcus pyogenes.","date":"1995","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/7806375","citation_count":72,"is_preprint":false},{"pmid":"11471550","id":"PMC_11471550","title":"ARP, a peptide derived from the stress-associated acetylcholinesterase variant, has hematopoietic growth promoting activities.","date":"2001","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/11471550","citation_count":72,"is_preprint":false},{"pmid":"12534372","id":"PMC_12534372","title":"Haematopoietic lineage cell-specific protein 1 (HS1) promotes actin-related protein (Arp) 2/3 complex-mediated actin polymerization.","date":"2003","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/12534372","citation_count":68,"is_preprint":false},{"pmid":"7512729","id":"PMC_7512729","title":"The Arabidopsis thaliana apurinic endonuclease Arp reduces human transcription factors Fos and Jun.","date":"1994","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7512729","citation_count":67,"is_preprint":false},{"pmid":"12780776","id":"PMC_12780776","title":"Actin-based motility of Burkholderia pseudomallei involves the Arp 2/3 complex, but not N-WASP and Ena/VASP proteins.","date":"2003","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/12780776","citation_count":63,"is_preprint":false},{"pmid":"7784207","id":"PMC_7784207","title":"Transcriptional activation by the orphan nuclear receptor ARP-1.","date":"1995","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/7784207","citation_count":61,"is_preprint":false},{"pmid":"17671267","id":"PMC_17671267","title":"A novel function for CRISP1 in rodent fertilization: involvement in sperm-zona pellucida interaction.","date":"2007","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/17671267","citation_count":60,"is_preprint":false},{"pmid":"12243744","id":"PMC_12243744","title":"Novel actin-related proteins Arp-T1 and Arp-T2 as components of the cytoskeletal calyx of the mammalian sperm head.","date":"2002","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/12243744","citation_count":60,"is_preprint":false},{"pmid":"16414181","id":"PMC_16414181","title":"Epididymal secreted protein Crisp-1 and sperm function.","date":"2006","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/16414181","citation_count":56,"is_preprint":false},{"pmid":"12384146","id":"PMC_12384146","title":"The stress-associated acetylcholinesterase variant AChE-R is expressed in human CD34(+) hematopoietic progenitors and its C-terminal peptide ARP promotes their proliferation.","date":"2002","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/12384146","citation_count":54,"is_preprint":false},{"pmid":"24934622","id":"PMC_24934622","title":"Arabidopsis ZDP DNA 3'-phosphatase and ARP endonuclease function in 8-oxoG repair initiated by FPG and OGG1 DNA glycosylases.","date":"2014","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24934622","citation_count":54,"is_preprint":false},{"pmid":"9271371","id":"PMC_9271371","title":"Functional domains of the human orphan receptor ARP-1/COUP-TFII involved in active repression and transrepression.","date":"1997","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9271371","citation_count":50,"is_preprint":false},{"pmid":"16467491","id":"PMC_16467491","title":"Identification of rat cysteine-rich secretory protein 4 (Crisp4) as the ortholog to human CRISP1 and mouse Crisp4.","date":"2006","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/16467491","citation_count":49,"is_preprint":false},{"pmid":"12829704","id":"PMC_12829704","title":"Identification of the p16-Arc subunit of the Arp 2/3 complex as a substrate of MAPK-activated protein kinase 2 by proteomic analysis.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12829704","citation_count":47,"is_preprint":false},{"pmid":"11432863","id":"PMC_11432863","title":"Identification of another actin-related protein (Arp) 2/3 complex binding site in neural Wiskott-Aldrich syndrome protein (N-WASP) that complements actin polymerization induced by the Arp2/3 complex activating (VCA) domain of N-WASP.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11432863","citation_count":45,"is_preprint":false},{"pmid":"21781197","id":"PMC_21781197","title":"Arabidopsis ARP endonuclease functions in a branched base excision DNA repair pathway completed by LIG1.","date":"2011","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21781197","citation_count":44,"is_preprint":false},{"pmid":"24781113","id":"PMC_24781113","title":"STM/BP-Like KNOXI Is Uncoupled from ARP in the Regulation of Compound Leaf Development in Medicago truncatula.","date":"2014","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/24781113","citation_count":44,"is_preprint":false},{"pmid":"7930578","id":"PMC_7930578","title":"Identification of the IgA-binding region in streptococcal protein Arp.","date":"1994","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/7930578","citation_count":43,"is_preprint":false},{"pmid":"1578147","id":"PMC_1578147","title":"Protein Arp and protein H from group A streptococci. Ig binding and dimerization are regulated by temperature.","date":"1992","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/1578147","citation_count":39,"is_preprint":false},{"pmid":"18554302","id":"PMC_18554302","title":"The sequence of the acidic repeat protein (arp) gene differentiates venereal from nonvenereal Treponema pallidum subspecies, and the gene has evolved under strong positive selection in the subspecies that causes syphilis.","date":"2008","source":"FEMS immunology and medical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/18554302","citation_count":39,"is_preprint":false},{"pmid":"17164533","id":"PMC_17164533","title":"Assessment of automatic ligand building in ARP/wARP.","date":"2006","source":"Acta crystallographica. Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/17164533","citation_count":38,"is_preprint":false},{"pmid":"8530503","id":"PMC_8530503","title":"ARP is a plasma membrane-associated Ras-related GTPase with remote similarity to the family of ADP-ribosylation factors.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8530503","citation_count":36,"is_preprint":false},{"pmid":"2062317","id":"PMC_2062317","title":"Binding properties of protein Arp, a bacterial IgA-receptor.","date":"1991","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/2062317","citation_count":35,"is_preprint":false},{"pmid":"9271383","id":"PMC_9271383","title":"The nuclear orphan receptors COUP-TF and ARP-1 positively regulate the trout estrogen receptor gene through enhancing autoregulation.","date":"1997","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9271383","citation_count":34,"is_preprint":false},{"pmid":"9020862","id":"PMC_9020862","title":"Isolation and characterization of the androgen-dependent mouse cysteine-rich secretory protein-1 (CRISP-1) gene.","date":"1997","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/9020862","citation_count":34,"is_preprint":false},{"pmid":"23898829","id":"PMC_23898829","title":"Comparison of CDC and sequence-based molecular typing of syphilis treponemes: tpr and arp loci are variable in multiple samples from the same patient.","date":"2013","source":"BMC microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/23898829","citation_count":33,"is_preprint":false},{"pmid":"21441424","id":"PMC_21441424","title":"Epididymal protein CRISP1 plays different roles during the fertilization process.","date":"2011","source":"Journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/21441424","citation_count":32,"is_preprint":false},{"pmid":"14711787","id":"PMC_14711787","title":"Bicarbonate is required for migration of sperm epididymal protein DE (CRISP-1) to the equatorial segment and expression of rat sperm fusion ability.","date":"2004","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/14711787","citation_count":32,"is_preprint":false},{"pmid":"17072959","id":"PMC_17072959","title":"Lack of association between UGT1A7, UGT1A9, ARP, SPINK1 and CFTR gene polymorphisms and pancreatic cancer in Italian patients.","date":"2006","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/17072959","citation_count":31,"is_preprint":false},{"pmid":"12777384","id":"PMC_12777384","title":"ARP-1/COUP-TF II determines hepatoma phenotype by acting as both a transcriptional repressor of microsomal triglyceride transfer protein and an inducer of CYP7A1.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12777384","citation_count":29,"is_preprint":false},{"pmid":"8245833","id":"PMC_8245833","title":"Conserved and variable regions in protein Arp, the IgA receptor of Streptococcus pyogenes.","date":"1993","source":"Journal of general microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/8245833","citation_count":26,"is_preprint":false},{"pmid":"16691012","id":"PMC_16691012","title":"ARP, the cleavable C-terminal peptide of \"readthrough\" acetylcholinesterase, promotes neuronal development and plasticity.","date":"2006","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/16691012","citation_count":25,"is_preprint":false},{"pmid":"29481619","id":"PMC_29481619","title":"Influence of the genetic background on the reproductive phenotype of mice lacking Cysteine-Rich Secretory Protein 1 (CRISP1).","date":"2018","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/29481619","citation_count":24,"is_preprint":false},{"pmid":"10386818","id":"PMC_10386818","title":"Cloning and characterization of an androgen-dependent acidic epididymal glycoprotein/CRISP1-like protein from the monkey.","date":"1999","source":"Journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/10386818","citation_count":24,"is_preprint":false},{"pmid":"7609634","id":"PMC_7609634","title":"Localization of transcripts of the related nuclear orphan receptors COUP-TF I and ARP-1 in the adult mouse brain.","date":"1995","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/7609634","citation_count":24,"is_preprint":false},{"pmid":"9461615","id":"PMC_9461615","title":"A short proximal promoter and the distal hepatic control region-1 (HCR-1) contribute to the liver specificity of the human apolipoprotein C-II gene. Hepatic enhancement by HCR-1 requires two proximal hormone response elements which have different binding specificities for orphan receptors HNF-4, ARP-1, and EAR-2.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9461615","citation_count":24,"is_preprint":false},{"pmid":"17510254","id":"PMC_17510254","title":"Molecular characterization and analysis of a gene encoding the acidic repeat protein (Arp) of Treponema pallidum.","date":"2007","source":"Journal of medical microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/17510254","citation_count":22,"is_preprint":false},{"pmid":"21593480","id":"PMC_21593480","title":"Evidence for the involvement of zinc in the association of CRISP1 with rat sperm during epididymal maturation.","date":"2011","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/21593480","citation_count":21,"is_preprint":false},{"pmid":"27836324","id":"PMC_27836324","title":"The major Arabidopsis thaliana apurinic/apyrimidinic endonuclease, ARP is involved in the plant nucleotide incision repair pathway.","date":"2016","source":"DNA repair","url":"https://pubmed.ncbi.nlm.nih.gov/27836324","citation_count":20,"is_preprint":false},{"pmid":"11191082","id":"PMC_11191082","title":"Expression of crisp-1 mRNA splice variants in the rat epididymis, and comparative analysis of the rat and mouse crisp-1 gene regulatory regions.","date":"2001","source":"Journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/11191082","citation_count":20,"is_preprint":false},{"pmid":"16169108","id":"PMC_16169108","title":"Production of bifunctional proteins by Aspergillus awamori: llama variable heavy chain antibody fragment (V(HH)) R9 coupled to Arthromyces ramosus peroxidase (ARP).","date":"2005","source":"Journal of biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/16169108","citation_count":19,"is_preprint":false},{"pmid":"28680579","id":"PMC_28680579","title":"The ARP 2/3 complex mediates endothelial barrier function and recovery.","date":"2017","source":"Pulmonary circulation","url":"https://pubmed.ncbi.nlm.nih.gov/28680579","citation_count":18,"is_preprint":false},{"pmid":"30914276","id":"PMC_30914276","title":"Genome-wide identification and expression analysis of dormancy-associated gene 1/auxin repressed protein (DRM1/ARP) gene family in Glycine max.","date":"2019","source":"Progress in biophysics and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/30914276","citation_count":18,"is_preprint":false},{"pmid":"19217389","id":"PMC_19217389","title":"\"Conditional Restraints\": Restraining the Free Atoms in ARP/wARP.","date":"2009","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/19217389","citation_count":17,"is_preprint":false},{"pmid":"10580147","id":"PMC_10580147","title":"Cloning and characterization of the rat Crisp-1 gene.","date":"1999","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/10580147","citation_count":17,"is_preprint":false},{"pmid":"20502914","id":"PMC_20502914","title":"A complex case of simple leaves: indeterminate leaves co-express ARP and KNOX1 genes.","date":"2010","source":"Development genes and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/20502914","citation_count":16,"is_preprint":false},{"pmid":"33559604","id":"PMC_33559604","title":"The accuracy of protein models automatically built into cryo-EM maps with ARP/wARP.","date":"2021","source":"Acta crystallographica. Section D, Structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/33559604","citation_count":15,"is_preprint":false},{"pmid":"9174057","id":"PMC_9174057","title":"Mutations in the arginine-rich protein gene (ARP) in pancreatic cancer.","date":"1997","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/9174057","citation_count":14,"is_preprint":false},{"pmid":"15304965","id":"PMC_15304965","title":"Detection of endonuclease III- and 8-oxoguanine glycosylase-sensitive base modifications in gamma-irradiated DNA and cells by the aldehyde reactive probe (ARP) assay.","date":"2004","source":"Journal of radiation research","url":"https://pubmed.ncbi.nlm.nih.gov/15304965","citation_count":14,"is_preprint":false},{"pmid":"10221773","id":"PMC_10221773","title":"Orphan receptor Arp-1 binds to the nucleotide sequence located between TATA box and transcriptional initiation site of the human angiotensinogen gene and reduces estrogen induced promoter activity.","date":"1999","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/10221773","citation_count":14,"is_preprint":false},{"pmid":"11891914","id":"PMC_11891914","title":"On the regulation of Crisp-1 mRNA expression and protein secretion by luminal factors presented in vivo by microperfusion of the rat proximal caput epididymidis.","date":"2002","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/11891914","citation_count":13,"is_preprint":false},{"pmid":"17785470","id":"PMC_17785470","title":"Characterization of an immunogenic outer membrane autotransporter protein, Arp, of Bartonella henselae.","date":"2007","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/17785470","citation_count":12,"is_preprint":false},{"pmid":"18703418","id":"PMC_18703418","title":"Association of the protein D and protein E forms of rat CRISP1 with epididymal sperm.","date":"2008","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/18703418","citation_count":12,"is_preprint":false},{"pmid":"12836256","id":"PMC_12836256","title":"Quantitation of DNA damage by an aldehyde reactive probe (ARP).","date":"2001","source":"Nucleic acids research. Supplement (2001)","url":"https://pubmed.ncbi.nlm.nih.gov/12836256","citation_count":12,"is_preprint":false},{"pmid":"11356572","id":"PMC_11356572","title":"Mobilisation of trehalose in mutants of the cyclic AMP signalling pathway, cr-1 (CRISP-1) and mcb (microcycle conidiation), of Neurospora crassa.","date":"2001","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/11356572","citation_count":12,"is_preprint":false},{"pmid":"33972689","id":"PMC_33972689","title":"ARP-T1-associated Bazex-Dupré-Christol syndrome is an inherited basal cell cancer with ciliary defects characteristic of ciliopathies.","date":"2021","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/33972689","citation_count":11,"is_preprint":false},{"pmid":"36204625","id":"PMC_36204625","title":"High-throughput nanopore sequencing of Treponema pallidum tandem repeat genes arp and tp0470 reveals clade-specific patterns and recapitulates global whole genome phylogeny.","date":"2022","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/36204625","citation_count":10,"is_preprint":false},{"pmid":"8152442","id":"PMC_8152442","title":"Interaction between streptococcal protein Arp and different molecular forms of human immunoglobulin A.","date":"1994","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8152442","citation_count":9,"is_preprint":false},{"pmid":"24101694","id":"PMC_24101694","title":"Presence of Arp specifically contributes to joint tissue edema associated with early-onset Lyme arthritis.","date":"2013","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/24101694","citation_count":9,"is_preprint":false},{"pmid":"19554349","id":"PMC_19554349","title":"Duplication of the Asymmetric Leaves1/Rough Sheath 2/Phantastica (ARP) gene precedes the explosive radiation of the Ruschioideae.","date":"2009","source":"Development genes and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/19554349","citation_count":9,"is_preprint":false},{"pmid":"21448475","id":"PMC_21448475","title":"LC-MS based quantification of 2'-ribosylated nucleosides Ar(p) and Gr(p) in tRNA.","date":"2011","source":"Chemical communications (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/21448475","citation_count":9,"is_preprint":false},{"pmid":"6228526","id":"PMC_6228526","title":"Alloimmune interactions of a lymphoproliferative disease-inducer gene Arp and linkage to Pep-7.","date":"1983","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/6228526","citation_count":8,"is_preprint":false},{"pmid":"12887093","id":"PMC_12887093","title":"Studies on the participation of epididymal sperm protein DE/CRISP-1 in egg activation.","date":"2003","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/12887093","citation_count":8,"is_preprint":false},{"pmid":"33750840","id":"PMC_33750840","title":"The less conserved metal-binding site in human CRISP1 remains sensitive to zinc ions to permit protein oligomerization.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33750840","citation_count":7,"is_preprint":false},{"pmid":"25917132","id":"PMC_25917132","title":"Spin-label CW microwave power saturation and rapid passage with triangular non-adiabatic rapid sweep (NARS) and adiabatic rapid passage (ARP) EPR spectroscopy.","date":"2015","source":"Journal of magnetic resonance (San Diego, Calif. : 1997)","url":"https://pubmed.ncbi.nlm.nih.gov/25917132","citation_count":7,"is_preprint":false},{"pmid":"10767373","id":"PMC_10767373","title":"Polymorphic variation of the ARP gene on 3p21 in Japanese esophageal cancer patients.","date":"2000","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/10767373","citation_count":6,"is_preprint":false},{"pmid":"25446841","id":"PMC_25446841","title":"Crisp1 and alopecia areata in C3H/HeJ mice.","date":"2014","source":"Experimental and molecular pathology","url":"https://pubmed.ncbi.nlm.nih.gov/25446841","citation_count":6,"is_preprint":false},{"pmid":"12614160","id":"PMC_12614160","title":"Transcriptional regulation of the nuclear gene encoding the alpha-subunit of the mammalian mitochondrial F1F0 ATP synthase complex: role for the orphan nuclear receptor, COUP-TFII/ARP-1.","date":"2003","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12614160","citation_count":6,"is_preprint":false},{"pmid":"10364473","id":"PMC_10364473","title":"Matrix-mediated changes in the expression of HNF-4alpha isoforms and in DNA-binding activity of ARP-1 in primary cultures of rat hepatocytes.","date":"1999","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10364473","citation_count":6,"is_preprint":false},{"pmid":"27105782","id":"PMC_27105782","title":"The Immunogenicity of CRISP1 Plasmid-Based Contraceptive Vaccine can be Improved When Using Chitosan Nanoparticles as the Carrier.","date":"2016","source":"American journal of reproductive immunology (New York, N.Y. : 1989)","url":"https://pubmed.ncbi.nlm.nih.gov/27105782","citation_count":5,"is_preprint":false},{"pmid":"39038222","id":"PMC_39038222","title":"Accelerated Degradation of DiXyl-α,ε-Lys-ARP via Interaction between Extra-Added Xylose and Monosubstituted Lys-ARPs during Maillard Reaction.","date":"2024","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39038222","citation_count":5,"is_preprint":false},{"pmid":"40245332","id":"PMC_40245332","title":"Deep Insight of the Mechanism for Nitrate-Promoted PFASs Defluorination in UV/Sulfite ARP: Activation of the Decarboxylation-Hydroxylation-Elimination-Hydrolysis Degradation Pathway.","date":"2025","source":"Environmental science & technology","url":"https://pubmed.ncbi.nlm.nih.gov/40245332","citation_count":5,"is_preprint":false},{"pmid":"1915280","id":"PMC_1915280","title":"Expression of the replication protein Arp of phasyl shows dual regulation by an antisense promoter.","date":"1991","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/1915280","citation_count":4,"is_preprint":false},{"pmid":"24638162","id":"PMC_24638162","title":"Phenotypic characterization of the CRISPA (ARP gene) mutant of pea (Pisum sativum; Fabaceae): a reevaluation.","date":"2014","source":"American journal of botany","url":"https://pubmed.ncbi.nlm.nih.gov/24638162","citation_count":4,"is_preprint":false},{"pmid":"32582022","id":"PMC_32582022","title":"ARP-1 Regulates the Transcriptional Activity of the Aromatase Gene in the Mouse Brain.","date":"2020","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/32582022","citation_count":3,"is_preprint":false},{"pmid":"12903194","id":"PMC_12903194","title":"Detection of NO-induced DNA lesions by the modified aldehyde reactive probe (ARP) assay.","date":"2002","source":"Nucleic acids research. Supplement (2001)","url":"https://pubmed.ncbi.nlm.nih.gov/12903194","citation_count":3,"is_preprint":false},{"pmid":"30286321","id":"PMC_30286321","title":"In silico screening of cancer-associated mutations in the HSA domain of BRG1 and its role in affecting the Arp-HSA sub-complex of SWI/SNF.","date":"2018","source":"Computational biology and chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30286321","citation_count":2,"is_preprint":false},{"pmid":"38828560","id":"PMC_38828560","title":"Overexpression of PD-L1 causes germ cell failure and infertility via CRISP1/PD-L1 interaction in mouse epididymis.","date":"2024","source":"Zygote (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38828560","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49277,"output_tokens":3284,"usd":0.098545},"stage2":{"model":"claude-opus-4-6","input_tokens":6659,"output_tokens":2739,"usd":0.152655},"total_usd":0.2512,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"Human CRISP1 is epididymis-specific at the mRNA level; the protein contains 16 conserved cysteine residues forming a modular structure with an N-terminal PR-like domain and a C-terminal cysteine-rich domain (CRD); all 16 cysteines are engaged in disulfide bonds, with the six N-terminal cysteines forming three intra-domain bonds, suggesting two discrete structural domains.\",\n      \"method\": \"cDNA cloning, Northern blot, N-terminal sequencing, ethyl maleimide treatment, proteolytic digestion of recombinant protein\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical characterization of disulfide bond pattern in recombinant protein with multiple orthogonal methods\",\n      \"pmids\": [\"8665901\", \"8562061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Rat CRISP1 (Protein DE) associates with the sperm surface in the epididymis and is lost during in vitro capacitation; exogenous CRISP1 inhibits capacitation-associated protein tyrosine phosphorylation in a dose-dependent manner, placing its decapacitating action upstream of cAMP production, and consequently inhibits the acrosome reaction.\",\n      \"method\": \"In vitro sperm capacitation assay, Western blot, exogenous protein addition, dose-response inhibition of tyrosine phosphorylation\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean functional assay with dose-response and upstream pathway placement, replicated across labs\",\n      \"pmids\": [\"12700197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human CRISP1 (ARP) is tightly associated with the surface of ejaculated sperm and mediates gamete fusion; antibodies against ARP inhibit penetration of zona-free hamster eggs without affecting sperm viability, motility, or acrosome reaction; complementary ARP-binding sites were identified on the surface of human eggs by indirect immunofluorescence.\",\n      \"method\": \"Sequential protein extraction, polyclonal antibody inhibition assay, zona-free egg penetration assay, indirect immunofluorescence of egg surface binding\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (antibody inhibition + egg surface binding), consistent with rodent data from other labs\",\n      \"pmids\": [\"11566719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CRISP1 participates in the initial step of sperm binding to the zona pellucida (ZP) in addition to gamete fusion; native CRISP1 binds directly to the ZP in a conformation-dependent (not glycan-dependent) manner that mimics sperm-ZP binding behavior; recombinant CRISP1 binds only to the oolema, not the ZP.\",\n      \"method\": \"In vitro fertilization inhibition assays (rat and mouse), anti-CRISP1 antibody, indirect immunofluorescence of protein binding to ZP and oolema, heat denaturation and deglycosylation controls\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple complementary functional and binding assays with rigorous controls\",\n      \"pmids\": [\"17671267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Crisp1 knockout mice produce sperm with reduced protein tyrosine phosphorylation during capacitation and significantly impaired ability to penetrate both ZP-intact and ZP-free eggs in vitro; in competition assays Crisp1-/- sperm show greater disadvantage in fusion ability, and residual fusion is further inhibited by exogenous CRISP1 or CRISP2, suggesting functional redundancy with another CRISP family member.\",\n      \"method\": \"Gene knockout (Crisp1-/- mice), in vitro fertilization assays, sperm tyrosine phosphorylation by Western blot, competition insemination assay, acrosome reaction assay\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — rigorous KO with multiple orthogonal phenotypic readouts and competition controls\",\n      \"pmids\": [\"18571638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Bicarbonate is required for CRISP1 (DE) migration from the dorsal region of the sperm head to the equatorial segment during capacitation, and sperm capacitated without bicarbonate—even if the anion is restored during gamete co-incubation—cannot fuse with eggs; cAMP analogs restore tyrosine phosphorylation but not DE migration, indicating a cAMP-independent bicarbonate requirement for CRISP1 redistribution.\",\n      \"method\": \"Sperm capacitation under defined ionic conditions, immunofluorescence tracking of DE localization, tyrosine phosphorylation Western blot, cAMP analog rescue experiments, egg penetration assay\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic dissection with multiple conditions and orthogonal readouts\",\n      \"pmids\": [\"14711787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The D and E isoforms of rat CRISP1 differ by an O-linked N-acetylgalactosamine on a threonine near the N-terminus of protein E; protein D associates transiently with sperm in a saturable, concentration-dependent manner consistent with its capacitation-inhibiting activity, while protein E becomes stably incorporated into sperm surface in the cauda epididymis and persists through capacitation.\",\n      \"method\": \"Tandem MS/MS, monosaccharide composition analysis, in vitro sperm-binding assays, Western blot, monoclonal antibody epitope characterization\",\n      \"journal\": \"Molecular and cellular endocrinology / Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mass spectrometry-based PTM identification combined with functional binding assays\",\n      \"pmids\": [\"16414181\", \"18703418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Zn2+ promotes association of the loosely bound population of CRISP1 with sperm by forming high-molecular-weight CRISP1-Zn2+ complexes; Zn2+ directly interacts with CRISP1 as evidenced by changes in tryptophan fluorescence emission spectra; EDTA prevents complex formation and sperm binding.\",\n      \"method\": \"In vitro sperm incubation with purified CRISP1 ± Zn2+/EDTA, Western blot, flow cytometry, epifluorescence microscopy, tryptophan fluorescence spectroscopy, native-PAGE\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct biophysical evidence of CRISP1-Zn2+ interaction combined with functional sperm-binding assay\",\n      \"pmids\": [\"21593480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CRISP1 is expressed by cumulus cells surrounding the egg and regulates sperm hyperactivation and orientation required for cumulus penetration; patch-clamp recordings show CRISP1 can directly modulate CatSper, the principal sperm Ca2+ channel involved in hyperactivation; Crisp1 KO females show impaired fertilization of cumulus-oocyte complexes due to sperm failure to penetrate the cumulus.\",\n      \"method\": \"Crisp1 KO females, fertilization assays with cumulus-oocyte complexes, sperm hyperactivation analysis, patch-clamp electrophysiology of sperm CatSper channel\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct electrophysiological measurement of channel modulation plus KO functional assay\",\n      \"pmids\": [\"26416967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crisp1-/- sperm on a homogeneous C57BL/6 background exhibit defects in progesterone-induced acrosome reaction, motility, and hyperactivation, as well as reduced cAMP and PKA substrate phosphorylation; treatment with a cAMP analog and phosphodiesterase inhibitor rescues these defects, placing CRISP1 upstream of the cAMP-PKA signaling pathway in capacitation.\",\n      \"method\": \"Backcrossed Crisp1-/- mice, acrosome reaction assay, sperm motility/hyperactivation analysis, cAMP measurement, PKA substrate phosphorylation Western blot, pharmacological rescue with cAMP analogs\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with pharmacological rescue precisely placing CRISP1 in cAMP-PKA pathway\",\n      \"pmids\": [\"29481619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Zn2+ induces oligomerization of human CRISP1 via the conserved His142 residue in the CAP domain; removal of Zn2+ by EDTA dissociates oligomers back to monomers; the isolated CAP domain alone undergoes the same Zn2+-dependent oligomerization, demonstrating that the CAP metal-binding site mediates this interaction.\",\n      \"method\": \"Recombinant MBP-tagged CRISP1 expression, in vitro Zn2+ addition, size-exclusion analysis, EDTA dissociation, His142 site-directed mutagenesis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with active-site mutagenesis demonstrating mechanism\",\n      \"pmids\": [\"33750840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Microinjection of DE (CRISP1) into eggs does not trigger Ca2+ oscillations or meiosis resumption, and does not modify oscillations induced by a sperm extract, arguing against a role for CRISP1 as a sperm-borne egg activation factor; its activity is restricted to the sperm-egg fusion step via interaction with egg surface binding sites.\",\n      \"method\": \"Egg incubation with DE protein, intracellular Ca2+ imaging, microinjection, meiosis resumption assay\",\n      \"journal\": \"Cellular and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional test ruling out egg activation role; single lab, single study\",\n      \"pmids\": [\"12887093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PD-L1 overexpression in mouse testis causes overexpression of CRISP1 in the epididymis; PD-L1 and CRISP1 can interact with each other; this leads to impaired sperm-zona pellucida binding and sperm-oocyte fusion, resulting in male infertility.\",\n      \"method\": \"Transgenic PD-L1 overexpression mouse model, CRISP1 protein expression analysis, sperm functional assays\",\n      \"journal\": \"Zygote\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, interaction evidence not rigorously characterized, limited mechanistic detail\",\n      \"pmids\": [\"38828560\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CRISP1 is an epididymally secreted, modular cysteine-rich protein that associates with sperm during maturation in two populations (loosely and tightly bound, distinguished by glycosylation state and zinc-dependent oligomerization); it acts as a decapacitation factor by inhibiting capacitation-associated tyrosine phosphorylation and cAMP-PKA signaling, redistributes to the equatorial segment upon capacitation in a bicarbonate-dependent manner, and subsequently participates in both sperm-zona pellucida binding and gamete fusion through interaction with complementary egg-surface sites; additionally, cumulus-cell-expressed CRISP1 modulates the sperm CatSper Ca2+ channel to regulate hyperactivation and sperm orientation during fertilization.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CRISP1 is an epididymally secreted, cysteine-rich secretory protein that functions at multiple steps of mammalian fertilization — from sperm capacitation to zona pellucida binding and gamete fusion. The protein associates with sperm in two populations distinguished by glycosylation and zinc-dependent oligomerization via the CAP domain His142 residue: a loosely bound, Zn²⁺-stabilized population that acts as a decapacitation factor by inhibiting cAMP-PKA signaling and tyrosine phosphorylation, and a tightly bound population that redistributes to the equatorial segment in a bicarbonate-dependent manner during capacitation to mediate sperm–zona pellucida binding and sperm–egg fusion through interaction with complementary egg-surface sites [PMID:12700197, PMID:16414181, PMID:33750840, PMID:14711787, PMID:11566719, PMID:17671267]. Crisp1 knockout sperm exhibit defective cAMP-PKA signaling, reduced hyperactivation, and impaired fertilization both at the zona and oolemma, with cAMP analog rescue confirming CRISP1 acts upstream of PKA [PMID:18571638, PMID:29481619]. Cumulus-cell-expressed CRISP1 additionally modulates the sperm CatSper Ca²⁺ channel to regulate hyperactivation required for cumulus penetration [PMID:26416967].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing the modular architecture of CRISP1 — the two-domain structure (PR-like/CAP + CRD) with all 16 cysteines engaged in disulfide bonds — provided the structural framework for understanding how distinct protein regions mediate different functions.\",\n      \"evidence\": \"cDNA cloning, Northern blot, proteolytic digestion and ethyl maleimide treatment of recombinant human CRISP1\",\n      \"pmids\": [\"8665901\", \"8562061\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure solved\", \"Functional contribution of individual disulfide bonds not tested\", \"CRD versus CAP domain function not yet dissected\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrating that CRISP1 on ejaculated sperm mediates gamete fusion via egg-surface binding sites established its direct fertilization role beyond epididymal coating.\",\n      \"evidence\": \"Polyclonal antibody inhibition of zona-free hamster egg penetration by human sperm; immunofluorescence of egg-surface CRISP1-binding sites\",\n      \"pmids\": [\"11566719\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the egg-surface receptor unknown\", \"Whether fusion role is conserved across species not systematically tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showing that exogenous CRISP1 inhibits capacitation-associated tyrosine phosphorylation upstream of cAMP production defined it as a decapacitation factor and placed its inhibitory action at the top of the signaling cascade.\",\n      \"evidence\": \"Dose-response inhibition of tyrosine phosphorylation during rat sperm in vitro capacitation\",\n      \"pmids\": [\"12700197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target mediating decapacitation not identified\", \"Mechanism by which CRISP1 suppresses cAMP production unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Revealing that CRISP1 redistribution from the dorsal head to the equatorial segment requires bicarbonate through a cAMP-independent pathway linked protein relocalization to fusion competence.\",\n      \"evidence\": \"Immunofluorescence tracking of CRISP1 localization under defined ionic conditions with cAMP analog rescue; rat sperm egg-penetration assay\",\n      \"pmids\": [\"14711787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of bicarbonate-driven redistribution unknown\", \"Whether membrane lipid remodeling drives CRISP1 migration not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identifying that a single O-GalNAc distinguishes the loosely bound (decapacitating) from the tightly bound (fusion-competent) CRISP1 population explained how one gene product fulfills two opposing roles on sperm.\",\n      \"evidence\": \"Tandem MS/MS glycosylation mapping; in vitro sperm binding assays comparing D and E isoforms\",\n      \"pmids\": [\"16414181\", \"18703418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzyme responsible for O-GalNAc addition not identified\", \"Whether human CRISP1 has analogous glycoform populations not confirmed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extending CRISP1's fertilization role to zona pellucida binding — in a conformation-dependent, glycan-independent manner — showed the protein participates in both primary gamete recognition and fusion.\",\n      \"evidence\": \"Native versus recombinant CRISP1 binding to ZP and oolema; IVF inhibition assays in rat and mouse\",\n      \"pmids\": [\"17671267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which ZP glycoprotein CRISP1 binds not determined\", \"Structural basis for conformation-dependent ZP binding unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Crisp1 knockout confirmed the protein's in vivo necessity for efficient fertilization and revealed functional redundancy with CRISP2 at the fusion step.\",\n      \"evidence\": \"Crisp1−/− mice; in vitro fertilization with ZP-intact and ZP-free eggs; competition insemination; exogenous CRISP1/CRISP2 inhibition\",\n      \"pmids\": [\"18571638\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Extent of CRISP1–CRISP2 redundancy in vivo not fully resolved\", \"Whether Crisp1/Crisp2 double KO is infertile not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating Zn²⁺-dependent oligomerization of CRISP1 and its role in promoting sperm association provided a biophysical mechanism for how epididymal zinc concentrations regulate decapacitation factor loading.\",\n      \"evidence\": \"In vitro Zn²⁺ incubation, tryptophan fluorescence spectroscopy, native-PAGE, EDTA dissociation, flow cytometry of sperm-bound CRISP1\",\n      \"pmids\": [\"21593480\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structure of CRISP1-Zn²⁺ oligomers not resolved\", \"In vivo zinc dynamics during epididymal transit not measured\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovering cumulus-cell-expressed CRISP1 and its direct modulation of the CatSper Ca²⁺ channel expanded CRISP1's role from a sperm-intrinsic factor to an oviductal guidance cue regulating hyperactivation.\",\n      \"evidence\": \"Crisp1 KO female fertilization assays with cumulus-oocyte complexes; patch-clamp electrophysiology of sperm CatSper\",\n      \"pmids\": [\"26416967\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CRISP1 activates or inhibits CatSper in physiological context not fully clarified\", \"Binding site on CatSper complex not mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Pharmacological rescue of Crisp1−/− sperm with cAMP analogs precisely placed CRISP1 upstream of the cAMP-PKA cascade, confirming the pathway hierarchy suggested by earlier biochemical studies.\",\n      \"evidence\": \"Backcrossed Crisp1−/− mice on C57BL/6; cAMP measurement, PKA substrate phosphorylation, pharmacological rescue of acrosome reaction and hyperactivation\",\n      \"pmids\": [\"29481619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target through which CRISP1 promotes cAMP production still unknown\", \"Whether CRISP1 regulates adenylyl cyclase or phosphodiesterase not distinguished\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapping the Zn²⁺-dependent oligomerization to the conserved His142 in the CAP domain provided the first residue-level mechanistic insight into CRISP1 self-association.\",\n      \"evidence\": \"Recombinant CAP domain expression, site-directed mutagenesis of His142, size-exclusion chromatography, EDTA reversibility\",\n      \"pmids\": [\"33750840\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full atomic structure of Zn²⁺-bound oligomer not determined\", \"Whether His142 mutation affects sperm binding or fertilization in vivo not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of the egg-surface CRISP1 receptor, the direct molecular target linking CRISP1 to cAMP production during capacitation, and the structural basis for conformation-dependent zona pellucida recognition.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Egg-surface CRISP1 receptor unidentified\", \"Mechanism connecting CRISP1 to adenylyl cyclase or phosphodiesterase activity unknown\", \"No high-resolution structure of CRISP1 or CRISP1-Zn²⁺ oligomer available\", \"CRISP1/CRISP2 double knockout fertility phenotype not characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 8, 9]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [2, 3, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 6, 7, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [2, 3, 4, 5, 8, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CATSPER1\",\n      \"CRISP2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}