Affinage

CFAP91

Cilia- and flagella-associated protein 91 · UniProt Q7Z4T9

Length
767 aa
Mass
90.0 kDa
Annotated
2026-06-09
19 papers in source corpus 5 papers cited in narrative 5 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

CFAP91 (MAATS1/AAT-1) is an axonemal scaffolding protein that organizes the radial spoke architecture of motile cilia and sperm flagella (PMID:32161152, PMID:36552811). Within the calmodulin- and spoke-associated complex (CSC), it physically partners with WDR66 and is required for the stable docking and positioning of radial spoke RS3 and the base of RS2 together with adjacent inner dynein arms; its loss depletes RS3-associated proteins (CFAP251/CFAP61, LRRC23) and the RS2-associated CFAP206, and it engages the molecular ruler protein CCDC39 that templates axonemal spacing (PMID:32161152, PMID:36552811, PMID:40931011). Loss of CFAP91 produces uncoordinated ciliary beating with dramatically reduced frequency in Tetrahymena and severe central-pair and radial-spoke defects, and in humans biallelic loss-of-function MAATS1 variants cause asthenoteratozoospermia while Cfap91-knockout mice show defective flagellum formation and male infertility (PMID:32161152, PMID:36552811, PMID:40931011). Proximity labeling in mature spermatozoa identifies the sperm-specific component EFCAB5 near CFAP91, whose own loss reduces sperm motility (PMID:40931011). Independently of its axonemal role, the testis-specific AAT-1alpha isoform localizes to mitochondria and assembles into a quaternary complex with AMY-1, S-AKAP84/AKAP149, and the PKA regulatory subunit RII, where it is phosphorylated by PKA and weakly stimulates PKA activity (PMID:12223483).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2002 Medium

    Established the first molecular interactions of the protein by identifying AAT-1 as a testis-specific AMY-1 binding partner that scaffolds a PKA-anchoring complex at mitochondria.

    Evidence Yeast two-hybrid, reciprocal Co-IP, subcellular colocalization, and in vitro/in vivo kinase assays in rat testis and HeLa cells

    PMID:12223483

    Open questions at the time
    • Does not connect the protein to ciliary/flagellar axoneme function
    • Functional consequence of PKA phosphorylation on the complex not defined
    • Relationship between the mitochondrial AAT-1alpha isoform and the axonemal pool unresolved
  2. 2005 Low

    Defined isoform diversity, showing alternative promoters generate variants with distinct cytoplasmic versus mitochondrial localization while retaining AMY-1 binding.

    Evidence Molecular cloning, immunofluorescence colocalization, and Co-IP in human cells

    PMID:15863901

    Open questions at the time
    • Single colocalization/pulldown method per isoform with no functional rescue
    • Physiological role of each isoform not established
    • No link to axonemal assembly
  3. 2020 High

    Reframed the gene as an axonemal CSC component by linking loss-of-function to human asthenoteratozoospermia and demonstrating conserved flagellar function.

    Evidence Exome sequencing of infertile men, sperm immunostaining and TEM, Co-IP for WDR66, and RNAi knockdown in Trypanosoma

    PMID:32161152

    Open questions at the time
    • Precise position within radial spoke architecture not yet mapped
    • Mechanism of WDR66 cooperation undefined
    • Full partner set not identified
  4. 2022 High

    Resolved the molecular role as a docking scaffold for RS3 and the RS2 base, defining the proteins whose assembly depends on it and the ruler protein it engages.

    Evidence Genetic knockout, proteomics, immunofluorescence, and swimming-speed assays in Tetrahymena

    PMID:36552811

    Open questions at the time
    • Direct versus indirect nature of the CCDC39 interaction not dissected
    • Structural mechanism of spoke docking unknown
    • Whether mitochondrial and axonemal functions share a common domain unresolved
  5. 2025 High

    Confirmed the RS3-scaffolding role in mammalian sperm in vivo and identified a sperm-specific proximal partner essential for motility.

    Evidence Cfap91 knockout mice, FLAG-BioID2 proximity labeling, Co-IP, and immunofluorescence in spermatozoa

    PMID:40931011

    Open questions at the time
    • Direct interaction versus proximity for EFCAB5 not distinguished
    • Structural model of the assembled RS3 scaffold lacking
    • How CFAP91 coordinates with the central pair complex not detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the testis-specific mitochondrial PKA-anchoring function relates mechanistically to the axonemal radial-spoke scaffolding role remains unresolved.
  • No structural model of CFAP91 within the radial spoke
  • Functional integration of mitochondrial AKAP complex and axonemal scaffolding undefined
  • Atomic-level basis of partner recruitment unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0060090 molecular adaptor activity 3
Localization
GO:0005739 mitochondrion 2 GO:0005856 cytoskeleton 2 GO:0005929 cilium 2
Pathway
R-HSA-1474165 Reproduction 2 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
AKAP149AMY-1CCDC39CFAP206CFAP251EFCAB5LRRC23WDR66
Complex memberships
AMY-1/AKAP149/PKA-RII quaternary complexcalmodulin- and spoke-associated complex (CSC)radial spoke RS3

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 AAT-1 (CFAP91 alias) was identified as a novel AMY-1-binding protein expressed specifically in the testis during spermatogenesis. AAT-1alpha forms a quaternary complex with AMY-1, S-AKAP84/AKAP149, and the regulatory subunit (RII) of cAMP-dependent protein kinase (PKA) in rat testis and HeLa cells, where AAT-1alpha is associated with RII via S-AKAP84/AKAP149. AAT-1alpha weakly stimulates PKA phosphorylation activity and is itself phosphorylated by PKA both in vivo and in vitro. AAT-1alpha co-localizes with AMY-1 in mitochondria. Yeast two-hybrid screening, co-immunoprecipitation, subcellular colocalization, in vivo and in vitro kinase assays The Journal of biological chemistry Medium 12223483
2005 Additional splicing isoforms of AAT-1 (AAT-1L, AAT-1M, AAT-1S) were identified, using a different promoter than AAT-1alpha/-beta/-gamma. All isoforms bind AMY-1 and co-localize with it in human cells. AAT-1L and AAT-1M are localized diffusely in the cytoplasm, while AAT-1S (like AAT-1alpha) localizes to a mitochondria-like structure, indicating isoform-specific subcellular localization. Molecular cloning, immunofluorescence/colocalization, co-immunoprecipitation Biological & pharmaceutical bulletin Low 15863901
2020 Biallelic loss-of-function variants in MAATS1 (encoding CFAP91) cause severe asthenoteratozoospermia in men. Immunostaining and TEM of patient sperm showed severe central pair complex (CPC) and radial spoke defects. WDR66 was confirmed as a physical and functional partner of CFAP91 in the calmodulin-associated and spoke-associated complex (CSC). RNAi knockdown of the Trypanosoma ortholog (TbCFAP91) impaired flagellar movement and caused CPC defects, confirming conserved axonemal localization and function. Exome sequencing, immunostaining, transmission electron microscopy, co-immunoprecipitation (WDR66 interaction), RNAi knockdown in Trypanosoma Journal of medical genetics High 32161152
2022 In Tetrahymena, Cfap91 is required for the stable docking/positioning of radial spoke RS3 and the base of RS2, and adjacent inner dynein arms. CFAP91-KO cells showed significantly diminished levels of RS3-specific proteins (Cfap61, Cfap251) and RS2-associated Cfap206. Cfap91 interacts with the molecular ruler protein Ccdc39. CFAP91-KO cilia beat in an uncoordinated manner with dramatically reduced beating frequency, causing cells to swim ~100 times slower than wild-type. Genetic knockout, proteomics/mass spectrometry, immunofluorescence microscopy, swimming speed measurements Cells High 36552811
2025 CFAP91 is an essential scaffolder of radial spoke RS3 assembly in mammalian spermatozoa. Cfap91 KO mice exhibit impaired sperm flagellum formation and male infertility. CFAP91 immunoprecipitates with RS3 proteins CFAP251 and LRRC23, whose localization is disrupted in Cfap91 KO sperm. Proximity labeling (BioID2) in mature spermatozoa identified EFCAB5 as a sperm-specific CFAP91-proximal component; Efcab5 KO males show reduced sperm motility and fertility. Knockout mouse model, FLAG-BioID2 proximity labeling, co-immunoprecipitation, immunofluorescence localization Nature communications High 40931011

Source papers

Stage 0 corpus · 19 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2023 Chloroquine resistance evolution in Plasmodium falciparum is mediated by the putative amino acid transporter AAT1. Nature microbiology 66 37169919
2014 The AAT1 locus is critical for the biosynthesis of esters contributing to 'ripe apple' flavour in 'Royal Gala' and 'Granny Smith' apples. The Plant journal : for cell and molecular biology 57 24661745
2020 Biallelic variants in MAATS1 encoding CFAP91, a calmodulin-associated and spoke-associated complex protein, cause severe astheno-teratozoospermia and male infertility. Journal of medical genetics 55 32161152
2010 Pentoxifylline attenuates transforming growth factor-beta1-stimulated elastogenesis in human tunica albuginea-derived fibroblasts part 2: Interference in a TGF-beta1/Smad-dependent mechanism and downregulation of AAT1. The journal of sexual medicine 37 20384945
1992 AAT1, a gene encoding a mitochondrial aspartate aminotransferase in Saccharomyces cerevisiae. Biochimica et biophysica acta 32 1482685
2016 Mechanical stretching stimulates collagen synthesis via down-regulating SO2/AAT1 pathway. Scientific reports 25 26880260
2002 AAT-1, a novel testis-specific AMY-1-binding protein, forms a quaternary complex with AMY-1, A-kinase anchor protein 84, and a regulatory subunit of cAMP-dependent protein kinase and is phosphorylated by its kinase. The Journal of biological chemistry 24 12223483
2020 Negative auto-regulation of sulfur dioxide generation in vascular endothelial cells: AAT1 S-sulfenylation. Biochemical and biophysical research communications 19 32087961
1982 Assignment of the gene for cytosolic alanine aminotransferase (AAT1) to human chromosome 8. Annals of human genetics 14 7114790
2022 Cfap91-Dependent Stability of the RS2 and RS3 Base Proteins and Adjacent Inner Dynein Arms in Tetrahymena Cilia. Cells 13 36552811
2018 Discovery of Anthocyanin Acyltransferase1 (AAT1) in Maize Using Genotyping-by-Sequencing (GBS). G3 (Bethesda, Md.) 13 30257861
1989 Characterization of AAT1: a gene involved in the regulation of amino acid transport in Saccharomyces cerevisiae. Journal of general microbiology 12 2697749
2022 Involvement of B-aat1 and Cbs in regulating mantle pigmentation in the Pacific oyster (Crassostrea gigas). Molecular biology reports 9 36335521
1998 Sex Differences in Polymorphism and Expression of AAT-1 in the Hiroshima Population of Buergeria buergeri (Anura, Rhacophoridae). Zoological science 8 18462026
2004 Geographic variability in expression of the sex-linked AAT-1 gene of the bell-ring frog, Buergeria buergeri. Journal of experimental zoology. Part B, Molecular and developmental evolution 7 15054861
2023 Transcription factor CgPOU3F4-like regulates expression of pheomelanin synthesis related gene CgB-aat1 in the Pacific oyster (Crassostrea gigas). Gene 5 36754175
2016 Complete Genome Sequence of Pseudomonas aeruginosa Phage AAT-1. Genome announcements 4 27563032
2005 Structure and characterization of AAT-1 isoforms. Biological & pharmaceutical bulletin 2 15863901
2025 Proximity labeling of axonemal protein CFAP91 identifies EFCAB5 that regulates sperm motility. Nature communications 1 40931011

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