Affinage

CATSPER4

Cation channel sperm-associated protein 4 · UniProt Q7RTX7

Length
472 aa
Mass
54.1 kDa
Annotated
2026-06-09
19 papers in source corpus 6 papers cited in narrative 5 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CATSPER4 is an essential pore-forming subunit of the sperm-specific CatSper Ca2+ channel required for the alkalinization-activated, voltage-sensitive Ca2+-selective current (ICatSper) that drives hyperactivated flagellar motility during capacitation (PMID:17227845, PMID:17344468). Targeted disruption in mice abolishes ICatSper, eliminates hyperactivated motility, and causes complete male infertility without disrupting spermatogenesis or initial motility, while the four CatSper subunits interact directly and form an interdependent heterotetrameric channel complex (PMID:17227845, PMID:17344468). Channel assembly depends on CATSPERθ (Tmem249), which acts as a scaffold for CATSPER4 during flagellar trafficking; loss of any CatSper transmembrane subunit, including CATSPER4, destabilizes CATSPERθ in spermatids, reflecting mutual interdependence for protein stability (PMID:37725640, PMID:36993167). Testis expression of Catsper4 is transcriptionally controlled by CREMτ binding to a cAMP-responsive element in its core promoter (PMID:41680579).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2007 High

    Establishing whether CATSPER4 is functionally required for the sperm Ca2+ current resolved its role as a genuine channel component rather than a predicted accessory protein.

    Evidence Targeted knockout mouse with ICatSper electrophysiology, sperm motility analysis, and co-immunoprecipitation of CatSper subunits

    PMID:17227845

    Open questions at the time
    • Did not define which CATSPER4 residues contribute to the conduction pore
    • Direct interactions shown by Co-IP do not establish subunit stoichiometry or architecture
  2. 2007 High

    Independent replication confirmed that CATSPER4 loss specifically eliminates hyperactivated motility under capacitating conditions, tying the channel to a defined motility transition.

    Evidence Independent knockout mouse with computer-assisted sperm analysis and capacitation assays

    PMID:17344468

    Open questions at the time
    • Does not separate CATSPER4's contribution from that of other CatSper subunits within the shared current
    • Mechanism linking Ca2+ entry to flagellar waveform change not addressed
  3. 2023 High

    Identifying CATSPERθ as a scaffold for CATSPER4 explained how the channel is assembled and trafficked to the flagellum and revealed reciprocal stability dependence among subunits.

    Evidence Multiple knockout mouse models, scaffold/Co-IP assays, immunofluorescence localization, and Western blotting

    PMID:36993167 PMID:37725640

    Open questions at the time
    • Sequence of assembly events and the trafficking route to the flagellum not fully resolved
    • Whether CATSPERθ contacts CATSPER4 directly or via an intermediate not defined
  4. 2026 Medium

    Mapping a functional CRE in the Catsper4 promoter and demonstrating CREMτ binding identified a transcriptional mechanism for testis-restricted expression.

    Evidence Promoter reporter/deletion assays, EMSA, ChIP, CRE mutagenesis, and CREMτ overexpression

    PMID:41680579

    Open questions at the time
    • Single lab, not yet independently replicated
    • Functional consequence of CREMτ loss on endogenous Catsper4 expression in vivo not established
    • Identity of the repressive elements in the deleted flanking regions unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular architecture of the human CATSPER4 pore and its quantitative contribution to ion selectivity within the assembled channel remain undefined.
  • No structural model of CATSPER4 within the human channel in the corpus
  • Human fertility phenotype of CATSPER4 variants not characterized in the available timeline

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0005215 transporter activity 1
Localization
GO:0005929 cilium 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-1474165 Reproduction 2 R-HSA-162582 Signal Transduction 1
Partners
CATSPER1CATSPER2CATSPER3CATSPERΘ/TMEM249CREMΤ
Complex memberships
CatSper channel

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Targeted disruption of murine CatSper4 abrogated ICatSper (the alkalinization-activated voltage-sensitive Ca2+-selective current), sperm hyperactivated motility, and male fertility without affecting spermatogenesis or initial motility. Direct protein interactions among all four CatSpers were demonstrated, establishing CatSper4 as an essential component of the flagellar CatSper channel complex. Knockout mouse model (targeted gene disruption), electrophysiology (ICatSper recording), sperm motility analysis, co-immunoprecipitation (direct protein interactions among CatSpers) Proceedings of the National Academy of Sciences of the United States of America High 17227845
2007 CatSper4 knockout male mice are completely infertile due to rapid loss of sperm motility and absence of hyperactivated motility under capacitating conditions, confirming CATSPER4 is required for hyperactivated motility during capacitation. Knockout mouse model (targeted gene disruption), computer-assisted sperm analysis (CASA), capacitation assay Biology of reproduction High 17344468
2003 In silico analysis identified coiled-coil protein-protein interaction domains in the C-terminal tails of all four CatSper proteins (including CatSper4), suggesting they form a heterotetrameric channel. CatSper4 carries a single channel-forming domain with a predicted pore-loop containing the consensus sequence TxDxW and is expressed in the testis. In silico gene identification, sequence analysis, expression evidence (testis expression) Reproductive biology and endocrinology : RB&E Low 12932298
2023 CATSPERθ (encoded by Tmem249) facilitates CatSper channel assembly by serving as a scaffold for the pore-forming subunit CATSPER4. CATSPERθ localizes at the interface of a CatSper dimer and can self-interact. Genetic ablation of any other CatSper transmembrane subunit (including CATSPER4) results in loss of CATSPERθ protein in spermatid cells during spermatogenesis, indicating mutual interdependence for protein stability and flagellar trafficking. Knockout mouse models (CATSPERθ and individual CatSper subunit KOs), co-immunoprecipitation/scaffold assay, immunofluorescence localization, Western blotting Proceedings of the National Academy of Sciences of the United States of America High 36993167 37725640
2026 The murine Catsper4 promoter contains a cAMP-responsive element (CRE) at +91 bp relative to the transcription start site. CREMτ binds to this CRE both in vitro and in vivo. A core promoter region spans -99 to +63 bp. Deletion of a 65 bp region at the 3'-end of the predicted promoter significantly enhanced transcription, and removal of a 239 bp 5'-flanking region also increased transcriptional activity. Promoter deletion/reporter assays, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), ChIP-seq data analysis (H3K4me3, H3K4me1, H3K27ac histone marks), site-directed mutagenesis of CRE, CREMτ overexpression Reproductive sciences (Thousand Oaks, Calif.) Medium 41680579

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 All four CatSper ion channel proteins are required for male fertility and sperm cell hyperactivated motility. Proceedings of the National Academy of Sciences of the United States of America 412 17227845
2007 Catsper3 and Catsper4 are essential for sperm hyperactivated motility and male fertility in the mouse. Biology of reproduction 145 17344468
2008 The mouse sperm proteome characterized via IPG strip prefractionation and LC-MS/MS identification. Proteomics 127 18340633
2003 Identification of human and mouse CatSper3 and CatSper4 genes: characterisation of a common interaction domain and evidence for expression in testis. Reproductive biology and endocrinology : RB&E 119 12932298
2011 A comprehensive gene mutation screen in men with asthenozoospermia. Fertility and sterility 31 21255775
2023 A CUG-initiated CATSPERθ functions in the CatSper channel assembly and serves as a checkpoint for flagellar trafficking. Proceedings of the National Academy of Sciences of the United States of America 20 37725640
2021 Detection of selection signatures for response to Aleutian mink disease virus infection in American mink. Scientific reports 18 33536540
2021 Effect of freeze-thawing process on lipid peroxidation, miRNAs, ion channels, apoptosis and global DNA methylation in ram spermatozoa. Reproduction, fertility, and development 18 34585662
2017 Histological analysis and identification of spermatogenesis-related genes in 2-, 6-, and 12-month-old sheep testes. Die Naturwissenschaften 18 28948304
2011 Molecular cloning, spatial and temporal expression analysis of CatSper genes in the Chinese Meishan pigs. Reproductive biology and endocrinology : RB&E 10 21970684
2023 Transcriptome Analysis Reveals Spermatogenesis-Related CircRNAs and LncRNAs in Goat Spermatozoa. Biochemical genetics 8 37815627
2023 Reduction of cryopreservation-induced structural, functional and molecular damages in ram sperm by hydrated C60 fullerene. Reproduction in domestic animals = Zuchthygiene 4 38038214
2023 A CUG-initiated CATSPERθ functions in the CatSper channel assembly and serves as a checkpoint for flagellar trafficking. bioRxiv : the preprint server for biology 3 36993167
2024 Identification of Potential Biomarkers Associated with Spermatogenesis in Azoospermia. Clinical laboratory 2 39506588
2022 In Silico Analysis of CatSper Family Genes and APOB Gene Regulation in Male Infertility. Advances in experimental medicine and biology 1 36472830
2026 <p>Echinacoside alleviates asthenozoospermia by upregulating Sox5‑mediated transcriptional activation of the CatSper gene</p>. Molecular medicine reports 0 41543154
2026 Molecular Characterization of the Murine Catsper4 Promoter and its Regulation by CREMτ. Reproductive sciences (Thousand Oaks, Calif.) 0 41680579
2026 Intraepididymal platelet-rich plasma improves semen cryoresistance via antioxidant, lipid and molecular modulation during the non-breeding season in rams. Veterinary research communications 0 41762345
2025 Integrated application of transcriptomics and metabolomics provides insights into sexual dimorphism in Apostichopus japonicus. Comparative biochemistry and physiology. Part D, Genomics & proteomics 0 41043282

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