Affinage

CFAP57

Cilia- and flagella-associated protein 57 · UniProt Q96MR6

Length
1250 aa
Mass
145.0 kDa
Annotated
2026-04-28
14 papers in source corpus 8 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CFAP57 is a conserved WD-repeat protein that functions as an extended axonemal scaffold required for the targeted assembly and docking of inner dynein arms within the 96 nm repeat of motile cilia and flagella. Cryo-electron tomography in Chlamydomonas shows that CFAP57 forms an elongated structure interconnecting multiple inner dynein arms (IDAs) and regulatory complexes, and its loss preferentially depletes single-headed IDAs including the 'g'-type (DHC7, DHC3) and 'd'-type (DHC2) dyneins (PMID:31483737, PMID:32764743). CFAP57 is a component of the inner dynein arm f (IDAf) complex through interaction with DNAH10, physically associates with the adaptor CCDC113 linking radial spokes and the nexin-dynein regulatory complex, and regulates MYH10 positioning and IFT88-dependent intraflagellar transport during flagellogenesis (PMID:40898283, PMID:39671309, PMID:41466333). Loss-of-function mutations in CFAP57—specifically disrupting its long isoform—cause reduced ciliary beat frequency, altered waveform, primary ciliary dyskinesia, and multiple morphological abnormalities of the sperm flagella (MMAF)-associated male infertility in humans and mice (PMID:32764743, PMID:36752199).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2018 Medium

    Positioning CFAP57 within the axonemal repeat architecture: Fap57p in Tetrahymena was shown to reside adjacent to the WD-repeat proteins Fap43p/Fap44p near the two-headed IDA I1, establishing that it occupies a defined structural niche within the 96 nm repeat.

    Evidence Genetic loss-of-function and immunofluorescence co-localization in Tetrahymena thermophila

    PMID:29687140

    Open questions at the time
    • No direct binding assay for FAP57 itself; adjacency inferred from Fap43/44 studies
    • Precise molecular contacts between FAP57 and neighboring complexes unresolved
    • Functional consequences of FAP57 loss not tested in this organism
  2. 2019 High

    Defining the structural and molecular function of CFAP57: cryo-ET with gold labeling in Chlamydomonas revealed that FAP57 forms an extended structure interconnecting multiple IDAs and regulatory complexes, and proteomics identified it as a discrete axonemal complex, establishing its role as a structural scaffold for IDA targeting within the 96 nm repeat.

    Evidence Insertional mutagenesis, cryo-electron tomography with epitope tagging and gold labeling, mass spectrometry proteomics in Chlamydomonas

    PMID:31483737

    Open questions at the time
    • Identity of all direct binding partners within the extended FAP57 structure not resolved
    • Whether the scaffold function is conserved in mammalian cilia not yet tested
  3. 2020 High

    Translating the scaffold function to human disease: CFAP57 localizes along the human ciliary axoneme, and a PCD-causing nonsense mutation prevents axonemal incorporation of the truncated protein, leading to reduced beat frequency and loss of specific IDAs ('g' and 'd' type), directly linking the Chlamydomonas mechanism to human ciliary disease.

    Evidence Whole-exome sequencing, immunofluorescence in human nasal epithelial cells, siRNA knockdown in hTECs, TMT-MS in Chlamydomonas mutants, high-speed video microscopy

    PMID:32764743

    Open questions at the time
    • Whether all single-headed IDA subtypes are equally dependent on CFAP57 remains unclear
    • Mechanism by which the truncated protein fails to incorporate into the axoneme is unknown
  4. 2022 Low

    In vivo validation in vertebrates: CRISPR F0 crispant zebrafish targeting cfap57 displayed ciliary phenotypes, providing cross-species confirmation that CFAP57 is required for normal ciliary function in a vertebrate model.

    Evidence CRISPR/Cas9 F0 crispant zebrafish phenotype screen

    PMID:36533556

    Open questions at the time
    • Screening-level validation without detailed mechanistic or ultrastructural analysis of cfap57 specifically
    • Mosaicism inherent to F0 crispants limits interpretation of severity
    • No IDA-specific assessment performed
  5. 2023 High

    Resolving isoform-specific function: the long CFAP57 isoform is specifically required for single-headed IDA assembly in sperm, as patient mutations and a CRISPR knock-in mouse model showed selective loss of the long isoform protein with corresponding IDA defects, while the short isoform remained intact.

    Evidence Whole-exome sequencing, CRISPR knock-in mouse model, electron microscopy, Western blot, immunofluorescence

    PMID:36752199

    Open questions at the time
    • Function of the short CFAP57 isoform is undefined
    • Whether isoform-specific requirements extend to respiratory cilia is untested
    • Structural basis for why the long isoform is selectively needed for single-headed IDAs is unknown
  6. 2024 Medium

    Identifying CFAP57 as part of a regulatory hub connecting axonemal sub-structures: CCDC113 was shown to bind CFAP57 and serve as an adaptor linking radial spokes, N-DRC, and doublet microtubules, placing CFAP57 within a multi-component regulatory network.

    Evidence Co-immunoprecipitation, mouse knockout model, electron microscopy, immunofluorescence

    PMID:39671309

    Open questions at the time
    • Whether CFAP57-CCDC113 interaction is direct or mediated by additional subunits not determined
    • Functional consequence of specifically disrupting the CFAP57-CCDC113 interface is unknown
  7. 2025 Medium

    Placing CFAP57 within the IDAf complex and expanding its interaction network: CFAP57 was confirmed as a DNAH10/IDAf complex component by co-IP, and separately shown to interact with MYH10 and regulate IFT88 expression, broadening its role from a static scaffold to a regulator of flagellar assembly and cargo transport.

    Evidence Co-immunoprecipitation, IP-mass spectrometry, immunoelectron microscopy, mouse knockout models, proteomics

    PMID:40898283 PMID:41466333

    Open questions at the time
    • Mechanism by which CFAP57 regulates IFT88 expression is unknown (transcriptional vs. post-translational)
    • Whether MYH10 interaction is direct or within a larger complex is unresolved
    • CFAP57's role in IDAf complex assembly vs. stability not distinguished

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis for how CFAP57 selectively targets specific IDA subtypes to defined positions within the 96 nm repeat, the function of its short isoform, and whether its IFT-regulatory role extends beyond spermatogenesis to respiratory and nodal cilia remain open questions.
  • No high-resolution structure of mammalian CFAP57 or its complexes
  • Short isoform function entirely uncharacterized
  • Tissue-specific requirements beyond sperm and respiratory cilia untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0005198 structural molecule activity 2
Localization
GO:0005929 cilium 4 GO:0005856 cytoskeleton 3
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 4
Partners
CCDC113CFAP91DNAH10FAP43FAP44IFT88MYH10
Complex memberships
Inner dynein arm f (IDAf) complex

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 FAP57/WDR65 (CFAP57 ortholog in Chlamydomonas) is required for targeting assembly of a subset of inner dynein arms (IDAs) to a specific location in the 96 nm axonemal repeat. Using cryo-electron tomography with epitope tagging and gold labeling, FAP57 forms an extended structure that interconnects multiple IDAs and regulatory complexes. High-resolution proteomics confirmed FAP57 forms a discrete complex within the axoneme. Insertional mutagenesis, cryo-electron tomography, epitope tagging with gold labeling, mass spectrometry proteomics Molecular biology of the cell High 31483737
2020 CFAP57 localizes throughout the ciliary axoneme in normal human nasal epithelial cells. A PCD-causing nonsense mutation (p.Arg588*) results in skipping of exon 11 (58 amino acids including portions of WD repeats), and the truncated protein fails to incorporate into the axoneme. Loss of CFAP57 causes reduced beat frequency and altered ciliary waveform. In Chlamydomonas fap57 mutants, the 'g' inner dyneins (DHC7 and DHC3) and 'd' inner dynein (DHC2) are reduced, implicating CFAP57 in inner dynein arm assembly. Whole exome sequencing, immunofluorescence localization, siRNA knockdown in hTECs, tandem mass tag mass spectrometry in Chlamydomonas mutants, high-speed video microscopy PLoS genetics High 32764743
2018 Fap57p (CFAP57 ortholog in Tetrahymena) is adjacent to the WD-repeat proteins Fap43p and Fap44p and is positioned near the two-headed inner dynein arm IDA I1. Loss of Fap43p or Fap44p alters ciliary waveform and reduces swimming speed, and these proteins are part of a complex adjacent to Fap57p. Genetic loss-of-function, ciliary motility analysis, immunofluorescence, co-localization in Tetrahymena thermophila Cellular and molecular life sciences : CMLS Medium 29687140
2023 CFAP57 loss-of-function mutations (p.R958* and p.R913*) disrupt inner dynein arm (IDA) assembly in sperm flagella, with single-headed IDAs preferentially affected. The long transcript-encoded CFAP57 protein is specifically lost in spermatozoa from affected individuals and Cfap57-mutant mice, while the short transcript product is unaffected, demonstrating isoform-specific function in sperm. Whole-exome sequencing, CRISPR knock-in mouse model, electron microscopy of sperm ultrastructure, immunofluorescence, Western blot JCI insight High 36752199
2025 CFAP57 interacts with MYH10 (non-muscle myosin IIB), identified by immunoprecipitation-mass spectrometry. In CFAP57-mutant sperm, MYH10 is mislocalized to the mid-piece and absent from the principal and end pieces. This mislocalization is accompanied by reduced expression of IFT88, a key intraflagellar transport component, establishing CFAP57 as a regulator of MYH10 positioning and IFT88-dependent flagellar assembly. Immunoprecipitation-mass spectrometry (IP-MS), immunofluorescence, immunoelectron microscopy, CRISPR-Cas9 mouse model Human genomics Medium 41466333
2024 CFAP57 interacts with CCDC113, which acts as an adaptor protein connecting radial spokes, the nexin-dynein regulatory complex (N-DRC), and doublet microtubules in the sperm axoneme. CCDC113 disruption impairs sperm flagella and head-tail coupling apparatus, and its binding partners include both CFAP57 and CFAP91. Co-immunoprecipitation, mouse knockout model, electron microscopy, immunofluorescence eLife Medium 39671309
2025 DNAH10 (inner arm dynein heavy chain) interacts with CFAP57 as part of the inner dynein arm f (IDAf) complex, confirmed by co-immunoprecipitation. Loss of DNAH10 leads to reduced expression of CFAP57 in patient cells and Dnah10 KO mice, indicating CFAP57 is a component of the IDAf complex. Co-immunoprecipitation, immunostaining, mouse knockout model, proteomics Orphanet journal of rare diseases Medium 40898283
2022 CRISPR/Cas9 F0 crispant zebrafish targeting cfap57 recapitulates ciliary phenotypes consistent with loss of ciliary function, validating CFAP57 as a cilia-associated gene required for normal ciliary function in vivo. CRISPR/Cas9 F0 crispant zebrafish, ciliary phenotype analysis Disease models & mechanisms Low 36533556

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 26 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 7 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