CFAP57 (cilia- and flagella-associated protein 57; also known as WDR65) is a conserved axonemal protein of motile cilia and sperm flagella, with an N-terminal WD40-repeat beta-propeller region and a long C-terminal coiled-coil region. In Chlamydomonas the ortholog FAP57 (IDA8/BOP2) forms an extended structure along the doublet microtubule that interconnects inner dynein arms with regulatory complexes, including the I1 dynein and the nexin-dynein regulatory complex region, and targets or stabilizes the binding of a subset of single-headed inner dynein arms (notably dyneins g and d) at their sites in the 96-nm axonemal repeat. Orthologs occur only in organisms that assemble inner dynein arms. In human airway epithelium CFAP57 is distributed along the ciliary axoneme, and loss of axonemal CFAP57 reduces ciliary beat frequency and alters waveform. A long isoform is required in sperm: biallelic loss-of-function variants cause spermatogenic failure 95, a male infertility disorder with multiple morphological abnormalities of the sperm flagellum and loss of inner dynein arms, and mouse models reproduce this phenotype. Affected men generally lack respiratory symptoms, although a homozygous CFAP57 variant that prevents axonemal incorporation was reported in one individual with primary ciliary dyskinesia.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005929 cilium | IDA GO_REF:0000052 | MODIFY | Summary: Human Protein Atlas immunofluorescence localizes CFAP57 to cilia. Reason: Correct but less specific than the evidence supports. CFAP57 is an axonemal component of motile cilia: it localizes throughout the axoneme of human nasal and tracheal motile cilia (PMID:32764743) and to sperm flagella (PMID:41466333), its orthologs are found only in organisms that assemble inner dynein arms (PMID:31483737), and it has no known role in primary cilia. GO:0031514 motile cilium (an is_a descendant of cilium) is the appropriate term; the more specific sperm flagellum location is already carried and accepted. Proposed replacements: motile cilium Supporting Evidence: PMID:32764743 In normal human nasal epithelial cells, CFAP57 localizes throughout the ciliary axoneme |
| GO:0005929 cilium | IEA GO_REF:0000117 | MODIFY | Summary: ARBA machine-learning prediction of cilium localization. Reason: Same claim and same assessment as the HPA cilium row: correct, but motile cilium (GO:0031514) is the specific location supported by direct human data (PMID:32764743). Proposed replacements: motile cilium Supporting Evidence: PMID:32764743 In normal human nasal epithelial cells, CFAP57 localizes throughout the ciliary axoneme |
| GO:0005930 axoneme | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to axoneme. Reason: Correct and core. CFAP57 localizes throughout the ciliary axoneme of human nasal cells and is enriched in isolated axonemes; a mutant form that fails to enter the axoneme causes ciliary dysfunction (PMID:32764743). In Chlamydomonas, FAP57 is an axonemal structure bound along the doublet microtubule (PMID:31483737). Supporting Evidence: PMID:32764743 The CFAP57 protein is strongly enriched in samples of detergent isolated ciliary axonemes PMID:31483737 Cryo-electron tomography coupled with epitope tagging and gold labeling reveal that FAP57 forms an extended structure that interconnects multiple IDAs and regulatory complexes |
| GO:0036126 sperm flagellum | IEA GO_REF:0000107 | ACCEPT | Summary: Transferred from mouse Cfap57 by Ensembl Compara orthology. Human data confirm CFAP57 in sperm flagella. Reason: Correct and supported by direct human evidence: CFAP57 localizes to sperm flagella (PMID:41466333), the long CFAP57 protein is lost from the spermatozoa of MMAF patients with loss-of-function variants, and its loss removes inner dynein arms from the sperm axoneme in human and mouse (PMID:36752199). Supporting Evidence: PMID:41466333 Immunofluorescence analysis confirmed that both MYH10 and CFAP57 localize to the sperm flagella PMID:36752199 Both CFAP57 mutations caused loss of the long transcript-encoded CFAP57 protein in spermatozoa from MMAF-affected individuals |
| GO:0036159 inner dynein arm assembly | IMP PMID:36752199 Loss-of-function mutations in CFAP57 cause multiple morpholo... | NEW | Summary: Proposed process. CFAP57 targets and stabilizes the binding of a subset of inner dynein arms in Chlamydomonas, and its loss disrupts inner dynein arm assembly in human and mouse sperm flagella. Reason: Participation: CFAP57 is not a dynein subunit, but it supplies the structure on which specific inner dynein arms dock. FAP57 forms an extended structure contacting multiple IDAs and stabilizes the binding of IDA g and, to a lesser extent, IDA d (PMID:31483737); patient sperm show a normal 9+2 axoneme lacking IDAs, and Cfap57 mutant mouse sperm lose single-headed IDAs although the dynein proteins are still synthesized (PMID:36752199). This is the scaffold case: the dynein assembles onto a site CFAP57 helps form. Comparator check (QuickGO, 2026-10-16): CCDC39 and CCDC40, axonemal docking/ruler proteins that specify attachment sites for IDAs and other complexes, carry GO:0036159 by IMP in human. The term is not an ancestor or descendant of the other terms proposed here or carried by CFAP57. Supporting Evidence: PMID:31483737 Collectively, these observations strongly suggested that FAP57 targets or stabilizes the attachment of these dyneins to their unique binding sites in the 96 nm repeat PMID:36752199 Subsequent examinations of the spermatozoa from Cfap57-mutant mice revealed that CFAP57 deficiency disrupted the inner dynein arm (IDA) assembly in sperm flagella and that single-headed IDAs were more likely to be affected PMID:36752199 Ultrastructural analysis of the sperm flagella from CFAP57-mutated individuals revealed the presence of a normal 9 + 2 structure with only IDAs’ absence |
| GO:0003341 cilium movement | IMP PMID:32764743 Mutation of CFAP57, a protein required for the asymmetric ta... | NEW | Summary: Proposed process. Loss of axonemal CFAP57 reduces ciliary beat frequency and alters waveform in human airway cells and in Chlamydomonas. Reason: Patient nasal cells lacking axonemal CFAP57 and CFAP57-knockdown tracheobronchial cells show reduced beat frequency and altered waveform, and fap57 Chlamydomonas swim slowly with altered waveforms (PMID:32764743). CFAP57 participates as an axonemal structural element that positions the inner dynein motors and interconnects them with regulatory complexes (PMID:31483737), not as a remote requirement. Comparator check (QuickGO, 2026-10-16): CCDC39 and CCDC40 carry GO:0003341 by IMP. The human airway evidence is a single PCD subject plus knockdown in cultured cells, so the term is proposed for motile cilia in general. GO:0120316 sperm flagellum assembly was not also proposed: an OLS hierarchicalAncestors query (2026-10-16) shows it is_a GO:0044458 motile cilium assembly and part_of GO:0030317 flagellated sperm motility, and GO:0030317 is_a GO:0060294 cilium movement involved in cell motility, which is_a GO:0003341 cilium movement, so the two would be an ancestor/descendant pair; it is raised as a question instead. Supporting Evidence: PMID:32764743 A reduced beat frequency and an alteration in ciliary waveform was observed PMID:32764743 Knockdown of CFAP57 in human tracheobronchial epithelial cells (hTECs) recapitulates these findings PMID:32764743 Two independent, insertional fap57 Chlamydomonas mutant strains show reduced swimming velocity and altered waveforms |
| GO:0005200 structural constituent of cytoskeleton | ISS PMID:31483737 FAP57/WDR65 targets assembly of a subset of inner arm dynein... | NEW | Summary: Proposed molecular function. CFAP57 has no known enzymatic activity; it is an extended WD40/coiled-coil structural element of the axoneme. Reason: CFAP57 has no molecular function annotation. Its established activity is structural, within the axoneme (a cytoskeletal structure): FAP57 forms an extended structure along the doublet that interconnects multiple IDAs and regulatory complexes (PMID:31483737). The term matches the CFAP61 review in this repository for axonemal scaffold subunits; because comparable proteins carry no informative MF in GOA, the choice is also raised as a question. Supporting Evidence: PMID:31483737 Cryo-electron tomography coupled with epitope tagging and gold labeling reveal that FAP57 forms an extended structure that interconnects multiple IDAs and regulatory complexes |
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Download this section (compressed HTML)Q: Do the long and short CFAP57 isoforms have tissue-specific roles, with the long isoform required in sperm and the short isoform sufficient in airway cilia? This would explain why most men with CFAP57 variants affecting only the long transcript lack respiratory symptoms, while a single PCD subject has been reported.
Q: Should CFAP57 also be annotated to GO:0120316 sperm flagellum assembly? Biallelic loss-of-function causes MMAF in human and mouse, but the primary defect appears to be inner dynein arm docking. An OLS hierarchicalAncestors query (2026-10-16) shows that GO:0120316 is_a GO:0044458 motile cilium assembly, part_of GO:0030317 flagellated sperm motility and part_of GO:0007286 spermatid development; through GO:0030317 (is_a GO:0060294 cilium movement involved in cell motility, is_a GO:0003341 cilium movement) it is a descendant of cilium movement, which is proposed here, and through GO:0007286 (part_of GO:0048515 spermatid differentiation, part_of GO:0007283 spermatogenesis) of spermatogenesis. If it were adopted it would replace cilium movement in core functions rather than be added beside it, at the cost of the airway evidence.
Q: Is GO:0005200 structural constituent of cytoskeleton the right molecular function for non-catalytic axonemal docking scaffolds such as CFAP57, CCDC39 and CCDC40, which currently carry no informative MF in GOA?
Experiment: Generate mice lacking only the short isoform or only the long isoform; analyze tracheal and sperm axonemes by cryo-electron tomography with subtomogram averaging to quantify inner dynein arm g/d occupancy, and measure ciliary beat frequency and sperm motility.
Hypothesis: The short CFAP57 isoform is sufficient for inner dynein arm docking in airway cilia but not in sperm flagella.
Type: mouse genetics / structural biology
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