Affinage

CFAP57

Cilia- and flagella-associated protein 57 · UniProt Q96MR6

Length
1250 aa
Mass
145.0 kDa
Annotated
2026-06-09
14 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

CFAP57 (FAP57/WDR65) is a conserved WD-repeat and coiled-coil axonemal protein that functions as a structural organizer of inner dynein arms (IDAs) within the 96 nm repeat of cilia and flagella (PMID:31483737, PMID:32764743). Cryo-electron tomography with epitope/gold labeling established that CFAP57 forms an extended structure interconnecting multiple IDA isoforms and regulatory complexes (PMID:31483737), and immunofluorescence places it throughout the ciliary axoneme (PMID:32764743). Loss of CFAP57 selectively impairs assembly and asymmetric targeting of a subset of IDAs—the 'g' (DHC7, DHC3) and 'd' (DHC2) inner dyneins in Chlamydomonas, and single-headed IDAs in mammalian sperm flagella (PMID:32764743, PMID:36752199). CFAP57 is integrated into a network of axonemal partners: it associates with the double-headed IDAf complex through direct interactions with DNAH10, DYNLL1, and CCDC73 (PMID:40898283), is bound by the adaptor CCDC113 that links radial spokes, the N-DRC, and doublet microtubules (PMID:39671309), and physically interacts with non-muscle myosin MYH10, whose correct flagellar localization and downstream IFT88 positioning depend on CFAP57 (PMID:41466333). CFAP57 expresses isoform-specific functions, with long-transcript loss-of-function mutations disrupting sperm IDA assembly and causing male infertility (MMAF), while axonemal-loading-defective variants cause primary ciliary dyskinesia (PMID:32764743, PMID:36752199).

Mechanistic history

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

    Before its molecular role was defined, it was unknown how CFAP57-family proteins relate to inner dynein arms; positioning the Tetrahymena ortholog within a discrete WD-repeat complex near IDA I1 established it as part of an IDA-associated assembly.

    Evidence Genetic loss-of-function and localization in Tetrahymena, with ciliary motility analysis

    PMID:29687140

    Open questions at the time
    • CFAP57 itself was not the primary mutagenesis target
    • Direct binding partners within the complex not biochemically defined
    • Phenotype attributed to Fap43p/Fap44p, not CFAP57
  2. 2019 High

    It was unclear what physical role CFAP57 plays in the axoneme; cryo-ET with gold labeling showed it forms an extended structure interconnecting multiple IDAs and regulatory complexes within the 96 nm repeat, defining it as a structural interconnector.

    Evidence Insertional mutagenesis, TMT proteomics, and cryo-electron tomography with epitope/gold labeling in Chlamydomonas

    PMID:31483737

    Open questions at the time
    • Atomic-resolution interaction interfaces not resolved
    • Which specific IDA isoforms it directly contacts not fully mapped
  3. 2020 High

    The disease relevance and IDA-targeting function were unproven; reciprocal human PCD genetics and Chlamydomonas mutants showed CFAP57 is required for axonemal loading and asymmetric targeting of 'g' and 'd' inner dyneins.

    Evidence Whole-exome sequencing of PCD patient, hTEC knockdown, Chlamydomonas mutant proteomics, immunofluorescence

    PMID:32764743

    Open questions at the time
    • Mechanism of axonemal docking/IFT binding inferred but not directly demonstrated
    • Paralog FBB7 compensation incompletely characterized
  4. 2023 High

    Whether CFAP57 isoforms have distinct functions was open; long-transcript loss-of-function mutations were shown to disrupt single-headed IDA assembly in sperm and cause male infertility, while the short isoform was spared, establishing isoform-specific roles.

    Evidence Whole-exome/Sanger sequencing in multiple families, CRISPR mouse model, sperm axoneme electron microscopy

    PMID:36752199

    Open questions at the time
    • Functional difference between long and short isoform products not biochemically defined
    • How isoform choice maps to tissue-specific phenotype unresolved
  5. 2024 Medium

    How CFAP57 is linked to other axonemal regulatory structures was unknown; CCDC113 was identified as an adaptor binding CFAP57 and connecting radial spokes, the N-DRC, and doublet microtubules.

    Evidence Co-immunoprecipitation, CCDC113 knockout mouse, structural analysis

    PMID:39671309

    Open questions at the time
    • Single-lab Co-IP without reciprocal CFAP57 pulldown reported here
    • Binding interface and stoichiometry not defined
  6. 2025 Medium

    The composition of the dynein complex containing CFAP57 and its non-dynein partners was incompletely defined; CFAP57 was shown to associate with DNAH10/DYNLL1/CCDC73 in the IDAf complex and to physically interact with MYH10, with CFAP57 loss mislocalizing MYH10 and disrupting IFT88.

    Evidence Co-IP and IP-MS, immunoelectron microscopy, CRISPR/Dnah10 and CFAP57 knockout mouse models

    PMID:40898283 PMID:41466333

    Open questions at the time
    • MYH10 interaction from single lab without reciprocal validation
    • Causal chain from MYH10 mislocalization to IFT88 disruption mechanistically unresolved
    • Direct vs. indirect nature of CFAP57–IFT88 relationship unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how CFAP57 mechanistically selects and docks specific IDA isoforms and how its interactions with myosin (MYH10) and IFT machinery are integrated during flagellar assembly.
  • No structural model of the CFAP57–IDA docking interface
  • Mechanism coupling CFAP57 to IFT88-dependent transport unknown
  • Functional distinction between long and short isoforms undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0008092 cytoskeletal protein binding 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005929 cilium 3 GO:0005856 cytoskeleton 2
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-1474165 Reproduction 2
Partners
CCDC113CCDC73DNAH10DYNLL1FAP43FAP44MYH10
Complex memberships
96 nm axonemal repeatinner dynein arm (IDAf complex)

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 FAP57/WDR65 (CFAP57) encodes a WD repeat, coiled-coil domain protein that forms a discrete complex in the flagellar axoneme. Cryo-electron tomography coupled with epitope tagging and gold labeling revealed that FAP57 forms an extended structure that interconnects multiple inner dynein arms (IDAs) and regulatory complexes within the 96 nm axonemal repeat. Insertional mutagenesis, high-resolution proteomics (TMT mass spectrometry), cryo-electron tomography, epitope tagging with gold labeling Molecular biology of the cell High 31483737
2020 CFAP57 localizes throughout the ciliary axoneme in normal human nasal epithelial cells. A PCD-causing nonsense variant (p.Arg588*) results in skipping of exon 11 (58 amino acids), producing a shorter mutant CFAP57 that fails to incorporate into the axoneme. Loss of the 58 amino acids (containing portions of WD repeats) disrupts axonemal loading, likely impairing IFT complex binding or docking. In Chlamydomonas fap57 mutants, 'g' inner dyneins (DHC7, DHC3) and 'd' inner dynein (DHC2) are reduced, while the FAP57 paralog FBB7 is increased, demonstrating that FAP57 is required for the asymmetric targeting of a subset of inner dynein arms. Whole exome sequencing, immunofluorescence (axonemal localization), CFAP57 knockdown in hTECs, Chlamydomonas insertional mutant analysis, TMT mass spectrometry PLoS genetics High 32764743
2018 In Tetrahymena thermophila, Fap57p (the CFAP57 ortholog) forms part of a complex adjacent to the WD-repeat proteins Fap43p and Fap44p, and is in proximity to the two-headed inner dynein arm IDA I1. Loss of Fap43p or Fap44p alters cilia waveform, beat stroke, and reduces swimming speed, and the ciliary localization of Fap43p and Fap44p is interdependent. Genetic loss-of-function in Tetrahymena, ciliary motility analysis, localization studies Cellular and molecular life sciences : CMLS Medium 29687140
2023 Loss-of-function mutations in the long transcript of CFAP57 (c.2872C>T, p.R958*; c.2737C>T, p.R913*) disrupt inner dynein arm (IDA) assembly in sperm flagella in humans and a CRISPR mouse model. Single-headed IDAs are preferentially affected. The short transcript-encoded CFAP57 protein is not affected by these mutations, indicating isoform-specific roles. Whole-exome sequencing, Sanger sequencing, CRISPR mouse model, electron microscopy of sperm axoneme JCI insight High 36752199
2025 CFAP57 interacts with MYH10 (non-muscle myosin II isoform) as identified by immunoprecipitation-mass spectrometry. Both proteins co-localize to sperm flagella. CFAP57 mutations cause mislocalization of MYH10 to the mid-piece region with absence from principal and end pieces. This mislocalization in turn disrupts expression/localization of IFT88, a key intraflagellar transport component required for flagellar assembly. Immunoprecipitation-mass spectrometry (IP-MS), immunofluorescence, immunoelectron microscopy, CRISPR-Cas9 mouse model Human genomics Medium 41466333
2025 DNAH10 (an inner arm dynein heavy chain) physically interacts with CFAP57, DYNLL1, and CCDC73 to form a double-headed inner dynein arm f (IDAf) complex. Co-IP confirmed these interactions. Loss of DNAH10 reduces CFAP57, DYNLL1, and CCDC73 expression in both patient samples and Dnah10 KO mice. Co-immunoprecipitation (Co-IP), Dnah10 knockout mouse model, immunostaining, proteomics Orphanet journal of rare diseases Medium 40898283
2024 CCDC113 binds to CFAP57 (and CFAP91) as demonstrated by co-IP, and functions as an adaptor protein connecting radial spokes, nexin-dynein regulatory complex (N-DRC), and doublet microtubules in the sperm axoneme. Co-immunoprecipitation, CCDC113 knockout mouse model, structural analysis eLife Medium 39671309

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Ciliary proteins Fap43 and Fap44 interact with each other and are essential for proper cilia and flagella beating. Cellular and molecular life sciences : CMLS 42 29687140
2020 Mutation of CFAP57, a protein required for the asymmetric targeting of a subset of inner dynein arms in Chlamydomonas, causes primary ciliary dyskinesia. PLoS genetics 39 32764743
2019 FAP57/WDR65 targets assembly of a subset of inner arm dyneins and connects to regulatory hubs in cilia. Molecular biology of the cell 32 31483737
2021 Proteomic Signature of Host Response to SARS-CoV-2 Infection in the Nasopharynx. Molecular & cellular proteomics : MCP 30 34400346
2023 Loss-of-function mutations in CFAP57 cause multiple morphological abnormalities of the flagella in humans and mice. JCI insight 27 36752199
2016 Integrated analysis miRNA and mRNA profiling in patients with severe oligozoospermia reveals miR-34c-3p downregulates PLCXD3 expression. Oncotarget 21 27486773
2022 Variable phenotypes and penetrance between and within different zebrafish ciliary transition zone mutants. Disease models & mechanisms 17 36533556
2011 Genomic strategy identifies a missense mutation in WD-repeat domain 65 (WDR65) in an individual with Van der Woude syndrome. American journal of medical genetics. Part A 12 21574244
2024 CCDC113 stabilizes sperm axoneme and head-tail coupling apparatus to ensure male fertility. eLife 9 39671309
2012 Transcriptional targeting in the airway using novel gene regulatory elements. American journal of respiratory cell and molecular biology 5 22447971
2026 A novel CFAP57 nonsense mutation causes asthenozoospermia in a consanguineous Emirati family. Molecular biology reports 0 41793497
2025 Anthraquinone-2-Carboxylic Acid Is a Potential Antiviral Candidate Against Influenza Viruses In Vitro and In Vivo. Viruses 0 40431640
2025 DNAH10 mutation cause primary ciliary dyskinesia with defects of IDAf complex assembly and lung fibrosis manifestation. Orphanet journal of rare diseases 0 40898283
2025 Mutations in CFAP57 disrupt the localization of MYH10 and IFT88, leading to flagellogenesis failure in humans and mice. Human genomics 0 41466333

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