CFAP206

CFAP206 is a conserved axonemal protein of motile cilia and flagella that functions as a microtubule-docking adapter required for radial spoke and inner dynein arm assembly (PMID:32376681, PMID:34255152). It localizes to the basal body and the ciliary axoneme, and its expression is controlled downstream of the master ciliogenesis transcription factor FOXJ1 (PMID:32376681). CFAP206 docks radial spoke and inner dynein arm components onto the axonemal microtubules; its loss eliminates the radial spoke proteins WDR66 and RSPH1, producing severe radial spoke and CASA (calmodulin/spoke-associated) complex defects (PMID:34255152). Functionally, loss of CFAP206 disrupts ciliary beat coordination and mucociliary clearance and renders sperm flagella immotile with ultrastructural defects (PMID:32376681, PMID:34255152). In humans, bi-allelic loss-of-function variants in CFAP206 cause male infertility with multiple morphological abnormalities of the flagella (MMAF), a connection recapitulated in knockout mice (PMID:34255152). Stable axonemal docking of CFAP206 at the RS2 radial spoke is itself dependent on Cfap91, which acts upstream to position and stabilize the protein (PMID:36552811).

1. 2020 High

   Established that CFAP206 is a FOXJ1-regulated motile-cilia protein localizing to the basal body and axoneme, with a role in radial spoke formation, answering where the protein acts and which structure it builds.

   Evidence Immunofluorescence localization, Xenopus CRISPR crispants (ciliary beat frequency and bead transport assays), and electron tomography of Cfap206 knockout mouse sperm flagella

   PMID:32376681

   Open questions at the time

   • Molecular interaction partners on the axoneme not identified
   • Mechanism by which loss enhances beat frequency yet impairs transport unresolved
   • Did not define which radial spoke components depend on CFAP206
2. 2021 High

   Defined CFAP206 as a microtubule-docking adapter for radial spoke and inner dynein arm components and linked its loss to human MMAF male infertility, establishing both molecular role and disease relevance.

   Evidence Exome sequencing of an infertile patient with a homozygous frameshift variant, patient-sperm immunostaining for WDR66 and RSPH1, and a CRISPR-Cas9 Cfap206 knockout mouse with motility, ultrastructure, and ICSI readouts

   PMID:34255152

   Open questions at the time

   • Direct physical interaction between CFAP206 and WDR66/RSPH1 not demonstrated biochemically
   • Structural basis of microtubule docking not resolved
   • Whether CFAP206 acts on dynein arms directly or indirectly via spoke integrity unclear
3. 2022 Medium

   Placed CFAP206 within the radial spoke assembly hierarchy by showing its RS2 docking and stability depend on the upstream factor Cfap91.

   Evidence Proteomics and immunofluorescence quantification of Cfap206 levels in Tetrahymena CFAP91-knockout cells

   PMID:36552811

   Open questions at the time

   • Single lab in Tetrahymena; mammalian dependence on CFAP91 not confirmed
   • Direct Cfap91-CFAP206 binding not shown
   • Order of recruitment relative to other RS2 subunits incomplete

• How CFAP206 physically engages microtubules and radial spoke/inner dynein arm subunits at atomic resolution, and the full recruitment hierarchy, remain undefined.
• No structural model of the CFAP206 docking interface
• No reconstituted biochemistry of CFAP206 with radial spoke or dynein components
• Mechanistic basis of altered beat frequency versus transport unresolved