Affinage

CFAP70

Cilia- and flagella-associated protein 70 · UniProt Q5T0N1

Length
1121 aa
Mass
125.7 kDa
Annotated
2026-06-09
16 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CFAP70 is a conserved axonemal protein of motile cilia and flagella that contributes both to the central apparatus and to outer dynein arm (ODA) regulation (PMID:30158508, PMID:33988244). It binds tightly to the axoneme through its N-terminus, which is necessary and sufficient for ciliary targeting, and resides stably at the base of the ODA, where loss of the protein impairs ODA activity and reduces ciliary beat frequency (PMID:30158508). In Chlamydomonas, the protein localizes specifically to the base of the C2a projection of the central apparatus, where it forms a complex with CFAP65 and MYCBPAP (FAP147); mutants lacking it lose most of the C2a projection along with these partners, defining the three proteins as core C2a components (PMID:33988244), an interaction independently corroborated through MYCBPAP interactome analyses in mouse testes (PMID:39092789, PMID:39704931). During spermatogenesis CFAP70 is required for flagellum biogenesis: it assists cytoplasmic preassembly of the calmodulin- and radial-spoke-associated complex (CSC), controls manchette-dependent localization of axoneme-related proteins, regulates OAT-associated protein expression, and maintains AKAP3 levels, while also associating with the ODA components DNAI1 and DNAI2 (PMID:37352829, PMID:37458246). Loss-of-function in humans and mice causes oligo-astheno-teratozoospermia with multiple morphological abnormalities of the flagella and male infertility (PMID:31621862, PMID:37352829).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2018 High

    Establishing that CFAP70 is a bona fide axonemal protein and pinpointing where it acts answered whether it is a structural axoneme component and how it contributes to motility.

    Evidence Stepwise axoneme protein extraction, truncation-fragment localization, ependymal knockdown with beat-frequency measurement, and cryo-ET of the Chlamydomonas fap70 mutant

    PMID:30158508

    Open questions at the time
    • Did not resolve whether the ODA-base localization reflects direct dynein binding
    • Molecular function of the C-terminal TPR domains left undefined
  2. 2019 Medium

    Patient sperm analysis tied CFAP70 loss to flagellar defects in humans and hinted at an interaction network, answering whether the gene is clinically relevant to male infertility.

    Evidence Immunofluorescence on patient sperm and whole-exome sequencing for variant identification

    PMID:31621862

    Open questions at the time
    • Co-absence with WDR66 is correlative, not a demonstrated physical interaction
    • Single-lab patient cohort
  3. 2021 High

    Defining the central apparatus C2a complex resolved the precise structural niche of the protein and its stable partners, recasting it from a generic axonemal factor to a defined complex subunit.

    Evidence Super-resolution SIM, cryo-EM, mass spectrometry of mutant axonemes, and Co-IP with HA-tagged FAP70 in Chlamydomonas

    PMID:33988244

    Open questions at the time
    • Reconciliation of C2a central-apparatus localization with the earlier ODA-base assignment not addressed
    • Stoichiometry and assembly order of the C2a complex unresolved
  4. 2023 High

    Mouse knockout and TPR-truncation models established the developmental requirement for CFAP70 in spermatid flagellum biogenesis and placed it within preassembly and transport pathways.

    Evidence CRISPR/Cas9 Cfap70-KO and truncation mice, sperm phenotyping, immunostaining, and protein expression analysis

    PMID:37352829

    Open questions at the time
    • Direct biochemical link between CFAP70 and CSC preassembly machinery not shown
    • Mechanism of manchette-dependent transport control undefined
  5. 2023 Medium

    Co-IP in mouse testis connected CFAP70 to ODA components DNAI1/DNAI2 and to AKAP3 maintenance, linking the central-apparatus protein to dynein-arm and scaffold regulation during spermiogenesis.

    Evidence Co-immunoprecipitation in Cfap70-deficient mouse testis, AKAP3 immunostaining, and spermatid morphological analysis

    PMID:37458246

    Open questions at the time
    • DNAI1/DNAI2 binding shown by Co-IP without reciprocal or direct-binding validation
    • Whether AKAP3 reduction is direct or secondary to broader assembly failure unresolved
  6. 2024 Medium

    Independent MYCBPAP interactome studies confirmed CFAP70 as a stable C2a complex partner in mammals, extending the Chlamydomonas complex assignment to mouse.

    Evidence Co-IP/MS interactome from MYCBPAP-tagged transgenic mice and endogenous Co-IP/MS in Mycbpap-/- testes

    PMID:39092789 PMID:39704931

    Open questions at the time
    • Direct binary interfaces among CFAP70, CFAP65 and MYCBPAP not mapped
    • Functional consequence of the mammalian C2a complex on motility not directly tested here

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single protein occupies both the central apparatus C2a projection and the ODA base, and the molecular role of its TPR domains in these contexts, remains unresolved.
  • No structural model reconciling C2a versus ODA-base localizations
  • TPR-domain ligands and biochemical function unidentified
  • Mechanism coupling central-apparatus residence to ODA activity regulation unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005856 cytoskeleton 2
Pathway
R-HSA-1474165 Reproduction 2 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
CFAP65DNAI1DNAI2MYCBPAP
Complex memberships
C2a central apparatus projection complex (CFAP70-CFAP65-MYCBPAP)

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 CFAP70 is a novel axoneme-binding protein that localizes at the base of the outer dynein arm (ODA) in motile cilia and flagella. Stepwise protein extraction from swine tracheal cilia showed CFAP70 binds tightly to the axoneme. The N-terminus (not the C-terminus bearing TPR domains) is required for ciliary localization, as shown by fluorescence microscopy of cultured ependyma expressing CFAP70 fragments. Knockdown of CFAP70 in cultured mouse ependyma reduced cilia beating frequency. Cryo-electron tomography of the Chlamydomonas FAP70 (CFAP70 ortholog) mutant showed the N-terminus resides stably at the base of the ODA, and fap70 mutants display defects in ODA activity and reduced flagellar motility. Stepwise axoneme protein extraction, fluorescence microscopy of truncation fragments, ependymal cell knockdown with beating frequency measurement, cryo-electron tomography of Chlamydomonas fap70 mutant Cells High 30158508
2021 In Chlamydomonas, FAP70 (CFAP70 ortholog) is exclusively located in the central apparatus (CA), specifically at the base of the C2a projection. Super-resolution structured illumination microscopy placed FAP70 in the CA rather than on doublet microtubules. Cryo-EM confirmed N-terminal localization at the base of C2a. fap70-1 mutant axonemes lack most of the C2a projection. Mass spectrometry of fap70-1 axonemes showed absence of FAP65 (CFAP65) and FAP147 (MYCBPAP) in addition to FAP70. Co-immunoprecipitation confirmed that FAP65 and FAP147 interact with HA-tagged FAP70, defining FAP70, FAP65, and FAP147 as the first components of the C2a projection. Super-resolution structured illumination microscopy, cryo-electron microscopy, mass spectrometry of mutant axonemes, co-immunoprecipitation with HA-tagged FAP70 Journal of cell science High 33988244
2019 Loss-of-function mutations in CFAP70 cause absence of ODA markers and central pair complex markers in human sperm flagella, as shown by immunofluorescence on patient sperm. CFAP70 protein was absent from sperm flagella in patients with the splice-site variant. Co-absence of CFAP70 staining was observed in sperm from patients mutated in WDR66 but not in patients mutated in ARMC2, FSIP2, or CFAP43, suggesting a possible interaction between CFAP70 and WDR66 axonemal components. Immunofluorescence on patient sperm cells; whole-exome sequencing for variant identification Human reproduction (Oxford, England) Medium 31621862
2023 CFAP70 is required for spermatid flagella biogenesis. Cfap70-KO mice are sterile due to oligo-astheno-teratozoospermia. Cfap70-truncated mice lacking 5–8 TPR repeats mimic human patient symptoms. CFAP70 regulates expression of OAT-associated proteins (e.g., QRICH2), assists cytoplasmic preassembly of the calmodulin- and radial-spoke-associated complex (CSC), and controls manchette localization of axoneme-related proteins. CRISPR/Cas9 Cfap70-KO and truncation mouse models, sperm phenotyping, immunostaining, protein expression analysis EBioMedicine High 37352829
2023 CFAP70 interacts with outer dynein arm proteins DNAI1 and DNAI2, as shown by co-immunoprecipitation in Cfap70-deficient mouse testis. Loss of CFAP70 also reduces levels of AKAP3 in sperm flagella. Cfap70-deficient spermatids exhibit club-shaped sperm heads and abnormal manchette disassembly, indicating CFAP70 participates in flagellum assembly and transport of flagellar components during spermiogenesis. CRISPR/Cas9 Cfap70-deficient mice, co-immunoprecipitation for DNAI1/DNAI2 interaction, immunostaining for AKAP3 levels, morphological analysis of spermatids Biology of reproduction Medium 37458246
2024 MYCBPAP interactome analysis using transgenic mice with tagged MYCBPAP revealed that MYCBPAP binds CFAP70 (along with CFAP65 and CCP110), identifying CFAP70 as a binding partner of MYCBPAP within the C2a central apparatus projection complex. Interactome analysis by co-immunoprecipitation/mass spectrometry using MYCBPAP-tagged transgenic mice Journal of cell science Medium 39092789
2024 Endogenous immunoprecipitation combined with mass spectrometry in Mycbpap-/- mouse testes confirmed MYCBPAP interacts with CFAP70 and CFAP65, further corroborating CFAP70 as a component of the central apparatus C2a projection complex associated with MYCBPAP. Endogenous co-immunoprecipitation combined with mass spectrometry in mouse testes Science China. Life sciences Medium 39704931

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 CFAP70 mutations lead to male infertility due to severe astheno-teratozoospermia. A case report. Human reproduction (Oxford, England) 50 31621862
2022 Identifying pleiotropic variants and candidate genes for fertility and reproduction traits in Holstein cattle via association studies based on imputed whole-genome sequence genotypes. BMC genomics 48 35484513
2018 CFAP70 Is a Novel Axoneme-Binding Protein That Localizes at the Base of the Outer Dynein Arm and Regulates Ciliary Motility. Cells 37 30158508
2020 Absence of murine CFAP61 causes male infertility due to multiple morphological abnormalities of the flagella. Science bulletin 23 36659204
2023 CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men. EBioMedicine 22 37352829
2021 Chlamydomonas FAP70 is a component of the previously uncharacterized ciliary central apparatus projection C2a. Journal of cell science 18 33988244
2021 Novel biallelic loss-of-function mutations in CFAP43 cause multiple morphological abnormalities of the sperm flagellum in Pakistani families. Asian journal of andrology 14 34100391
2016 The transcription factor, Nuclear factor, erythroid 2 (Nfe2), is a regulator of the oxidative stress response during Danio rerio development. Aquatic toxicology (Amsterdam, Netherlands) 14 27716579
2023 Experimental and molecular support for Cfap70 as a causative gene of 'multiple morphological abnormalities of the flagella' with male infertility†. Biology of reproduction 11 37458246
2024 Cilia Plays a Pivotal Role in the Hypersecretion of Airway Mucus in Mice. Current molecular pharmacology 6 40231527
2024 Integrated miRNA and mRNA Sequencing Reveals the Sterility Mechanism in Hybrid Yellow Catfish Resulting from Pelteobagrus fulvidraco (♀) × Pelteobagrus vachelli (♂). Animals : an open access journal from MDPI 3 38891632
2024 MYCBPAP is a central apparatus protein required for centrosome-nuclear envelope docking and sperm tail biogenesis in mice. Journal of cell science 3 39092789
2024 Comprehensive analysis of chromosomal breakpoints and candidate genes associated with male infertility: insights from cytogenetic studies and expression analyses. Mammalian genome : official journal of the International Mammalian Genome Society 3 39358566
2024 Homozygous deleterious variants in MYCBPAP induce asthenoteratozoospermia involving abnormal acrosome biogenesis, manchette structure and sperm tail assembly in humans and mice. Science China. Life sciences 2 39704931
2025 The essential role of cytoskeleton and ciliary abnormalities in the development of congenital pulmonary airway malformations. Pediatric surgery international 0 41264116
2025 Potential Therapeutic Targets for Neuroblastoma Screened through Mendelian Randomization Analysis. Archives of Iranian medicine 0 41778435

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