Affinage

CABYR

Calcium-binding tyrosine phosphorylation-regulated protein · UniProt O75952

Length
493 aa
Mass
52.8 kDa
Annotated
2026-06-09
20 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CABYR is a polymorphic, calcium-binding structural protein of the sperm flagellar fibrous sheath that organizes a phosphorylation-regulated scaffold required for sperm motility (PMID:11820818, PMID:27802166). Its calcium-binding activity is restricted to the CABYR-A region and is acquired during capacitation in a phosphorylation-dependent manner, being abolished by dephosphorylation (PMID:11820818, PMID:16139264). CABYR oligomerizes—first forming dimers of CABYR-A-only and CABYR-A/B isoforms, then higher-order oligomers that assemble into the ribs and longitudinal columns of the fibrous sheath—and uses its RII dimerization domain to scaffold AKAP3 and AKAP4, while binding Ropporin through a distinct, RII-independent region (PMID:16139264, PMID:20731842, PMID:21240291). Additional partners place CABYR within a glycolytic and signaling microenvironment of the principal piece, including the calcium-binding partner FSCB, PGK2, and the GSK3β kinase that phosphorylates CABYR within its extensin-like domain (PMID:15752768, PMID:17855365, PMID:30972801). In vivo, CABYR is essential for fibrous sheath integrity, correct axonemal doublet organization, and progressive, normally chiral sperm motility, with knockout males being severely subfertile (PMID:27802166, PMID:36142535). Beyond its testis role, non-testis CABYR-a/b isoforms act in cancer cells upstream of an Akt-dependent survival program and a YAP/p73/DR5 apoptosis axis (PMID:24362251, PMID:26843620).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2002 High

    Established CABYR as a novel calcium-binding flagellar protein whose calcium binding is coupled to capacitation-associated phosphorylation, linking a structural sperm protein to capacitation signaling.

    Evidence 45Ca overlay on 2D gels with alkaline phosphatase controls, fibrous sheath immunolocalization, and cDNA/domain analysis in human sperm

    PMID:11820818

    Open questions at the time
    • Specific calcium-binding residues/motif not biochemically mapped
    • Identity of the kinase(s) phosphorylating CABYR during capacitation not defined
    • Functional consequence of calcium binding for sheath assembly untested
  2. 2003 Medium

    Confirmed mouse CABYR as the authentic orthologue with conserved domain architecture and flagellar localization, enabling genetic study in a model organism.

    Evidence cDNA/genomic cloning, Northern blot, immunofluorescence localization, and sequence comparison in mouse

    PMID:12801634

    Open questions at the time
    • No functional assay in mouse at this stage
    • Single-lab sequence-based domain assignment
  3. 2005 High

    Localized calcium-binding activity to the CABYR-A coding region and showed CABYR-B isoforms assemble structurally into fibrous sheath ribs and columns, separating the calcium-sensing and structural functions to distinct regions.

    Evidence Calcium overlay on recombinant CABYR-A vs CABYR-B, region-specific immunofluorescence and immunoelectron microscopy

    PMID:16139264

    Open questions at the time
    • How calcium binding to CABYR-A modulates oligomer or sheath behavior not shown
    • Stoichiometry of CABYR-A vs CABYR-B isoforms in the sheath unresolved
  4. 2005 High

    Identified GSK3β as a kinase and interaction partner acting through the proline-rich extensin-like domain, and showed this domain mediates CABYR dimerization, defining a phosphorylation input distinct from capacitation tyrosine phosphorylation.

    Evidence Yeast two-hybrid, GST pull-down, and in vitro kinase assay with phosphosite mapping on non-testis CABYR variants

    PMID:15752768

    Open questions at the time
    • Functional consequence of GSK3β phosphorylation on CABYR in sperm not established
    • Relationship between extensin-domain dimerization and RII-domain oligomerization unclear
  5. 2007 High

    Defined FSCB as a direct, PKA-phosphorylated and calcium-binding CABYR partner, extending the fibrous sheath complex to additional calcium- and kinase-regulated components.

    Evidence Co-immunoprecipitation, in vitro PKA assay, calcium overlay, and immunoelectron microscopy in mouse sperm

    PMID:17855365

    Open questions at the time
    • Domain of CABYR mediating FSCB binding not mapped
    • Functional role of the CABYR–FSCB complex in motility untested
  6. 2010 High

    Resolved the oligomerization hierarchy and showed the RII domain is required for AKAP3/AKAP4 binding but dispensable for Ropporin binding, defining how CABYR uses separable interfaces to nucleate distinct sheath complexes.

    Evidence Immunoprecipitation, yeast two-hybrid, and RII-deletion constructs with Western blot and immunofluorescence

    PMID:20731842

    Open questions at the time
    • Ropporin-binding region not positively mapped
    • Order of complex assembly during spermiogenesis not resolved
  7. 2011 High

    Confirmed the CABYR–AKAP3–Ropporin scaffold in human sperm with reciprocal Co-IP and MS, corroborating RII-dependent AKAP3 binding versus RII-independent Ropporin binding across species.

    Evidence Reciprocal Co-IP of insoluble fibrous sheath proteins with MS and Western blot, plus yeast two-hybrid in human sperm

    PMID:21240291

    Open questions at the time
    • Higher-order architecture of the assembled complex not structurally defined
  8. 2011 Medium

    Extended CABYR interactions beyond sperm by identifying isoform-specific binding of CABYR-a to α-enolase in cancer cells, hinting at a glycolytic/metabolic association of non-testis isoforms.

    Evidence Co-immunoprecipitation from cancer cell lysates with Western blot confirmation

    PMID:21274509

    Open questions at the time
    • Single Co-IP without reciprocal pull-down
    • Functional consequence of the α-enolase interaction not tested
  9. 2013 Medium

    Placed cancer CABYR-a/b upstream of Akt in a survival pathway, showing knockdown reduces Akt signaling and confers chemosensitivity, with constitutively active Akt rescuing resistance.

    Evidence shRNA knockdown with constitutively active Akt rescue, pathway Western blots, viability/apoptosis assays, and xenografts in NSCLC

    PMID:24362251

    Open questions at the time
    • Mechanism linking CABYR-a/b to Akt activation undefined
    • Single lab; relevance to sperm CABYR function unclear
  10. 2016 High

    Demonstrated in vivo that CABYR is essential for fibrous sheath integrity and axonemal organization, causally connecting the scaffold to sperm ultrastructure and motility.

    Evidence CRISPR-Cas9 knockout mice with fertility assays, electron microscopy, and motility analysis

    PMID:27802166

    Open questions at the time
    • Which CABYR domain/partner interaction underlies the structural defect not dissected
    • Calcium-binding contribution to the phenotype not isolated
  11. 2016 Medium

    Defined a second cancer axis by placing CABYR-a/b upstream of YAP/p73/DR5, where depletion activates YAP and sensitizes cells to TRAIL-induced apoptosis.

    Evidence shRNA knockdown with YAP/p73 loss- and gain-of-function, double deletion, phospho-Western blots, and apoptosis assays in lung cancer cells

    PMID:26843620

    Open questions at the time
    • Direct molecular link between CABYR-a/b and YAP phosphorylation unknown
    • Single lab
  12. 2019 Medium

    Added PGK2 as a CABYR partner in human sperm, reinforcing association of CABYR with glycolytic enzymes in the flagellum.

    Evidence Co-IP of recombinant CBP86-IV with MS, reverse Co-IP in sperm lysate, and yeast two-hybrid

    PMID:30972801

    Open questions at the time
    • Binding interface not mapped
    • Functional role in flagellar energy metabolism untested
  13. 2022 Medium

    Refined the motility phenotype by showing CABYR contributes to, but is not absolutely required for, clockwise sperm swim-path chirality under defined nucleotide conditions.

    Evidence Digital holographic microscopy of detergent-extracted KO vs WT mouse sperm with cAMP/ADP/ATP/Mg2+ manipulation

    PMID:36142535

    Open questions at the time
    • Single method and lab
    • Mechanism by which the fibrous sheath sets chirality unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How capacitation-dependent calcium binding to CABYR-A mechanistically regulates oligomerization, partner assembly, and fibrous sheath remodeling remains unresolved, as does the molecular link between non-testis CABYR-a/b isoforms and the Akt and YAP/p73 pathways.
  • No structural model of CABYR or its complexes
  • Calcium-binding consequence for sheath assembly untested in vivo
  • Direct effector linking CABYR-a/b to Akt/YAP not identified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005929 cilium 3 GO:0005856 cytoskeleton 2
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1474165 Reproduction 1
Partners
AKAP3AKAP4ENO1FSCBGSK3BPGK2ROPN1
Complex memberships
fibrous sheath

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 CABYR is a calcium-binding, tyrosine-phosphorylated fibrous sheath protein localizing to the principal piece of the human sperm flagellum; calcium binding to its acidic 86-kDa isoforms is acquired during in vitro capacitation and is dependent on phosphorylation (abolished by alkaline phosphatase treatment). The protein contains an RII dimerization domain homologous to PKA regulatory subunit RII, a putative EF hand-like motif, PXXP modules, and multiple predicted tyrosine phosphorylation sites. 45Ca overlay on 2D gels, immunofluorescence localization to fibrous sheath, alkaline phosphatase dephosphorylation assay, cDNA cloning and domain analysis Developmental biology High 11820818
2003 Mouse CABYR is the authentic orthologue of human CABYR; it localizes to the principal piece of mouse epididymal spermatozoa, contains two coding regions (CR-A and CR-B), an RII dimerization domain, PXXP motifs, and extensin-like regions conserved with human CABYR. Cloning of mouse cDNA and genomic DNA, immunofluorescence localization, Northern blot, sequence comparison Gene Medium 12801634
2005 Calcium binding in CABYR is restricted to the CABYR-A coding region; recombinant CABYR-A binds calcium in vitro whereas recombinant CABYR-B does not. CABYR-B-containing isoforms are translated during spermiogenesis and assemble into the ribs and longitudinal columns of the fibrous sheath in the flagellar principal piece. Calcium overlay assay on recombinant proteins, immunofluorescence and immunoelectron microscopy with region-specific antibodies Developmental biology High 16139264
2005 Two non-testis-specific CABYR variants (281 and 379) interact with GSK3β via a proline-rich extensin-like domain (confirmed by yeast two-hybrid and GST pull-down), form dimers through that domain, and serve as substrates for GSK3β phosphorylation within the extensin-like domain (phosphorylation sites mapped by kinase assay). Yeast two-hybrid screening with GSK3β as bait, GST pull-down assay, in vitro kinase assay with phosphorylation-site mapping Biochemical and biophysical research communications High 15752768
2007 FSCB (fibrous sheath CABYR binding protein) is a direct binding partner of CABYR; FSCB is phosphorylated by protein kinase A in vitro and at native sites in mouse sperm, and is itself a calcium-binding protein (calcium overlay assay). Co-immunoprecipitation (identification of CABYR–FSCB interaction), in vitro PKA phosphorylation assay, calcium overlay assay, immunoelectron microscopy The Journal of biological chemistry High 17855365
2010 CABYR isoforms oligomerize by forming dimers (80 kDa CABYR-A-only with 50 kDa CABYR-A/B variant), and then larger oligomers that assemble into the fibrous sheath. The RII domain of CABYR is required for binding to AKAP3/AKAP4 (deletion of RII domain abolishes this interaction) but is not required for binding to Ropporin, indicating CABYR uses a distinct region to bind Ropporin. Immunoprecipitation, yeast two-hybrid assay, RII domain deletion constructs, immunofluorescence, Western blot Reproductive biology and endocrinology High 20731842
2011 CABYR binds AKAP3 and Ropporin in the human sperm fibrous sheath; reciprocal co-immunoprecipitation confirmed the CABYR–AKAP3 complex, and yeast two-hybrid confirmed both interactions. CABYR binds AKAP3 via its RII domain but binds Ropporin through regions outside the RII-like domain. Reciprocal co-immunoprecipitation of insoluble fibrous sheath proteins followed by mass spectrometry and Western blot, yeast two-hybrid assay Asian journal of andrology High 21240291
2011 CABYR-a (but not CABYR-c) interacts with α-enolase in vivo in cancer cell lines, identifying α-enolase as a binding partner specific to this isoform. Co-immunoprecipitation from cancer cell lysates, Western blot confirmation Oncology reports Medium 21274509
2013 Knockdown of CABYR-a/b in non-small cell lung cancer cells reduces Akt phosphorylation (constitutively active Akt), decreases phospho-GSK-3β (Ser9), and increases p53 and p27, leading to increased chemosensitivity and apoptosis; rescue with constitutively active Akt partially restores drug resistance, placing CABYR-a/b upstream of Akt in a cancer cell survival pathway. shRNA knockdown, constitutively active Akt rescue transfection, Western blot for pathway components, cell viability and apoptosis assays in vitro and in vivo (xenograft) Molecular cancer research Medium 24362251
2016 CABYR is essential for fibrous sheath integrity and progressive sperm motility; Cabyr-knockout male mice are severely subfertile with disorganized fibrous sheath ribs/columns and abnormal doublet microtubule configuration in the axoneme, demonstrating that CABYR is required for correct axonemal organization through its role in fibrous sheath assembly. CRISPR-Cas9 knockout in mice, fertility assays, electron microscopy of sperm ultrastructure, motility analysis Journal of cell science High 27802166
2016 Depletion of CABYR-a/b sensitizes lung cancer cells to TRAIL-induced apoptosis by decreasing YAP S127 phosphorylation (activating YAP) and increasing YAP/p73-mediated DR5 upregulation; double deletion of YAP and p73 abolishes DR5 upregulation and TRAIL-induced apoptosis in CABYR-a/b-knockdown cells, placing CABYR-a/b upstream of the YAP/p73/DR5 axis. shRNA knockdown of CABYR-a/b, loss- and gain-of-function of YAP and p73, Western blot for phospho-YAP/p73/DR5, apoptosis assays, agonistic DR5 antibody treatment Oncotarget Medium 26843620
2019 CABYR (CBP86-IV isoform) binds phosphoglycerate kinase 2 (PGK2) in human spermatozoa, confirmed by reverse co-immunoprecipitation and yeast two-hybrid assay. Co-immunoprecipitation of recombinant CBP86-IV expressed in E. coli with mass spectrometry identification, reverse Co-IP in human sperm lysate, yeast two-hybrid Andrologia Medium 30972801
2022 CABYR is required for correct sperm swim-path chirality (clockwise path); in CABYR-knockout sperm, path chirality is preserved under defined cAMP/ADP/ATP/Mg2+ conditions using digital holographic microscopy, indicating CABYR in the fibrous sheath contributes to but is not absolutely required for path chirality. Digital holographic microscopy of detergent-extracted mouse sperm, Cabyr-knockout comparison, pharmacological manipulation of cAMP/ADP/ATP/Mg2+ International journal of molecular sciences Medium 36142535
2010 CABYR knockdown in human embryo 293T cells does not significantly affect NF-κB gene expression, indicating CABYR is not functionally linked to the NF-κB signaling pathway in this context (negative result). shRNA-mediated CABYR knockdown, quantitative real-time PCR for NF-κB expression World journal of gastroenterology Low 20954286

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 CABYR, a novel calcium-binding tyrosine phosphorylation-regulated fibrous sheath protein involved in capacitation. Developmental biology 160 11820818
2016 CABYR is essential for fibrous sheath integrity and progressive motility in mouse spermatozoa. Journal of cell science 46 27802166
2011 CABYR binds to AKAP3 and Ropporin in the human sperm fibrous sheath. Asian journal of andrology 39 21240291
2007 FSCB, a novel protein kinase A-phosphorylated calcium-binding protein, is a CABYR-binding partner involved in late steps of fibrous sheath biogenesis. The Journal of biological chemistry 38 17855365
2007 CABYR is a novel cancer-testis antigen in lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 28 17317841
2010 CABYR isoforms expressed in late steps of spermiogenesis bind with AKAPs and ropporin in mouse sperm fibrous sheath. Reproductive biology and endocrinology : RB&E 27 20731842
2005 Characterization of two non-testis-specific CABYR variants that bind to GSK3beta with a proline-rich extensin-like domain. Biochemical and biophysical research communications 26 15752768
2013 Knockdown of CABYR-a/b increases chemosensitivity of human non-small cell lung cancer cells through inactivation of Akt. Molecular cancer research : MCR 20 24362251
2016 Depletion of CABYR-a/b sensitizes lung cancer cells to TRAIL-induced apoptosis through YAP/p73-mediated DR5 upregulation. Oncotarget 19 26843620
2017 Molecular study of human sperm RNA: Ropporin and CABYR in asthenozoospermia. Journal of endocrinological investigation 17 29247344
2005 Translation and assembly of CABYR coding region B in fibrous sheath and restriction of calcium binding to coding region A. Developmental biology 15 16139264
2011 Expression of the sperm fibrous sheath protein CABYR in human cancers and identification of α-enolase as an interacting partner of CABYR-a. Oncology reports 10 21274509
2003 Splicing in murine CABYR and its genomic structure. Gene 10 12801634
2012 The expression and effects the CABYR-c transcript of CABYR gene in hepatocellular carcinoma. Bulletin du cancer 9 22285430
2023 FTHL17, PRM2, CABYR, CPXCR1, ADAM29, and CABS1 are highly expressed in colon cancer patients and are regulated in vitro by epigenetic alterations. Heliyon 5 38187237
2022 cAMP and the Fibrous Sheath Protein CABYR (Ca2+-Binding Tyrosine-Phosphorylation-Regulated Protein) Is Required for 4D Sperm Movement. International journal of molecular sciences 5 36142535
2015 Low-expressed testis-specific calcium-binding protein CBP86-IV (CABYR) is observed in idiopathic asthenozoospermia. World journal of urology 5 25717016
2019 Testis-specific calcium-binding protein CBP86-IV (CABYR) binds with phosphoglycerate kinase 2 in vitro and in vivo experiment. Andrologia 2 30972801
2021 The cancer testis antigens CABYR-a/b and CABYR-c are expressed in a subset of colorectal cancers and hold promise as targets for specific immunotherapy. Oncotarget 0 33747357
2010 CABYR RNAi plasmid construction and NF-κB signal transduction pathway. World journal of gastroenterology 0 20954286

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