Affinage

CFAP91

Cilia- and flagella-associated protein 91 · UniProt Q7Z4T9

Length
767 aa
Mass
90.0 kDa
Annotated
2026-04-28
19 papers in source corpus 5 papers cited in narrative 5 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CFAP91 is an axonemal scaffolding protein that localizes to the base of radial spokes RS2 and RS3 in motile cilia and sperm flagella, where it is required for stable docking of RS3, proper assembly of adjacent inner dynein arms, and coordinated ciliary beating (PMID:36552811, PMID:40931011). In sperm, CFAP91 physically interacts with RS3 components CFAP251, LRRC23, and the sperm-specific proximal protein EFCAB5; loss of CFAP91 disrupts RS3 protein localization and causes severe flagellar structural defects leading to male infertility in both mice and humans carrying biallelic loss-of-function variants (PMID:32161152, PMID:40931011). A testis-enriched isoform (AAT-1α) additionally participates in a mitochondria-associated quaternary complex with AMY-1, S-AKAP84/AKAP149, and PKA-RII, and is phosphorylated by PKA, linking CFAP91 to cAMP-dependent signaling in the testis (PMID:12223483).

Mechanistic history

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

    The initial identification of AAT-1 (CFAP91) as a testis-specific AMY-1-binding protein established that it participates in a mitochondria-associated quaternary complex with AMY-1, S-AKAP84/AKAP149, and PKA-RII, linking the protein to cAMP/PKA signaling in germ cells.

    Evidence Yeast two-hybrid, reciprocal co-immunoprecipitation, immunofluorescence colocalization, and in vitro/in vivo PKA phosphorylation assays in rat testis and HeLa cells

    PMID:12223483

    Open questions at the time
    • Quaternary complex characterized by a single laboratory; independent validation in other systems lacking
    • Physiological significance of PKA phosphorylation of AAT-1 for sperm function not determined
    • Relationship of mitochondrial complex to axonemal role was unknown
  2. 2005 Medium

    Characterization of multiple AAT-1 isoforms revealed isoform-specific subcellular targeting, with AAT-1α localizing to mitochondria and longer isoforms distributing diffusely in the cytoplasm, suggesting functional diversification.

    Evidence Isoform cloning, co-immunoprecipitation, and immunofluorescence in human cells

    PMID:15863901

    Open questions at the time
    • Single-lab study; isoform-specific functions not tested by loss-of-function approaches
    • Which isoforms are relevant for axonemal versus mitochondrial roles was unresolved
  3. 2020 High

    The discovery that biallelic MAATS1 (CFAP91) variants cause central pair complex and radial spoke defects in human sperm — and that CFAP91 physically interacts with WDR66 in the calmodulin-associated/spoke-associated complex — established CFAP91 as an essential structural component of the sperm axoneme and linked it to human male infertility.

    Evidence Exome sequencing of infertile men, transmission electron microscopy, immunostaining, co-immunoprecipitation, and RNAi knockdown in Trypanosoma brucei

    PMID:32161152

    Open questions at the time
    • Precise position of CFAP91 within the axonemal repeat and its relationship to specific radial spokes not yet mapped
    • Mechanism by which loss of CFAP91 disrupts the central pair complex was unclear
  4. 2022 High

    Genetic knockout in Tetrahymena pinpointed CFAP91 to the base of radial spokes RS2 and RS3, demonstrating that it is required for RS3 docking and adjacent inner dynein arm assembly, and that it interacts with the molecular ruler protein CCDC39 — thereby resolving its structural position within the 96-nm axonemal repeat.

    Evidence CFAP91-KO Tetrahymena, quantitative proteomics of axonemes, co-immunoprecipitation with CCDC39, motility analysis

    PMID:36552811

    Open questions at the time
    • Whether mammalian CFAP91 occupies the same position was not directly shown
    • Direct structural data (cryo-ET) of CFAP91 within the repeat unit was lacking
  5. 2025 High

    Cfap91 knockout mice confirmed the protein as an essential RS3 scaffold in mammalian sperm, identified CFAP251, LRRC23, and the sperm-specific EFCAB5 as direct or proximal interaction partners, and validated EFCAB5 as functionally important for sperm motility and fertility.

    Evidence Cfap91 and Efcab5 knockout mice, FLAG immunoprecipitation, BioID2 proximity labeling, immunofluorescence

    PMID:40931011

    Open questions at the time
    • High-resolution structural model of the CFAP91-RS3 scaffold complex is not yet available
    • Whether CFAP91 has additional roles in somatic motile cilia beyond the ciliate model remains untested in mammals
    • Functional connection between the mitochondrial PKA-associated complex and the axonemal scaffolding role is unexplored

Open questions

Synthesis pass · forward-looking unresolved questions
  • A structural understanding of how CFAP91 bridges the molecular ruler (CCDC39/CCDC40) to RS3 and inner dynein arms, and whether the mitochondrial PKA-associated role of CFAP91 is functionally independent from its axonemal scaffolding function, remain open questions.
  • No cryo-EM or cryo-ET structure of CFAP91 in the axonemal repeat
  • Relationship between mitochondrial/PKA signaling function and flagellar assembly function unresolved
  • Role of CFAP91 in primary ciliary dyskinesia or respiratory cilia not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2
Localization
GO:0005929 cilium 3 GO:0005739 mitochondrion 2 GO:0008092 cytoskeletal protein binding 2
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 3
Partners
AKAP1AMY1CCDC39CFAP251EFCAB5LRRC23WDR66
Complex memberships
AMY-1/S-AKAP84/PKA-RII quaternary complexCalmodulin-associated and spoke-associated complex (CSC)

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 CFAP91 (encoded by MAATS1) is a calmodulin-associated and spoke-associated complex (CSC) protein essential for normal sperm flagellum structure; biallelic loss-of-function variants in MAATS1 cause severe central pair complex (CPC) and radial spoke defects in human sperm. WDR66 was identified as a physical and functional partner of CFAP91 within the CSC by co-immunoprecipitation and immunostaining. Exome sequencing, transmission electron microscopy, immunostaining, co-immunoprecipitation, RNAi knockdown of TbCFAP91 in Trypanosoma Journal of medical genetics High 32161152
2022 Tetrahymena Cfap91 localizes to the base of radial spokes RS2 and RS3 and is required for stable docking/positioning of RS3 and the base of RS2, as well as adjacent inner dynein arms. Loss of Cfap91 reduces levels of RS3-specific proteins (Cfap61, Cfap251) and RS2-associated Cfap206, and Cfap91 interacts with the molecular ruler protein Ccdc39. CFAP91-KO cilia beat in an uncoordinated manner with dramatically reduced frequency, causing severely impaired swimming. Genetic knockout in Tetrahymena, proteomics, immunofluorescence microscopy, co-immunoprecipitation with Ccdc39 Cells High 36552811
2025 CFAP91 is an essential scaffolder of radial spoke RS3 assembly in mammalian sperm flagella. 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. BioID2 proximity labeling identified EFCAB5 as a sperm-specific CFAP91-proximal component; Efcab5 KO males show reduced sperm motility and fertility. Cfap91 knockout mouse, FLAG/BioID2 proximity labeling, immunoprecipitation, immunofluorescence localization, Efcab5 knockout Nature communications High 40931011
2002 AAT-1 (CFAP91) was identified as a testis-specific AMY-1-binding protein that 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. AAT-1alpha localizes to mitochondria, weakly stimulates PKA phosphorylation activity, and is itself phosphorylated by PKA both in vivo and in vitro. Yeast two-hybrid screening, co-immunoprecipitation, colocalization by immunofluorescence, in vitro and in vivo PKA phosphorylation assay The Journal of biological chemistry Medium 12223483
2005 Multiple AAT-1 (CFAP91) isoforms (AAT-1L, AAT-1M, AAT-1S, plus alpha/beta/gamma) were characterized; all isoforms bind AMY-1. AAT-1alpha and AAT-1S localize to a mitochondria-like structure, while AAT-1L and AAT-1M are diffusely cytoplasmic, indicating isoform-specific subcellular targeting. Isoform cloning, co-immunoprecipitation, immunofluorescence colocalization in human cells Biological & pharmaceutical bulletin Medium 15863901

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 62 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 55 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 54 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 31 1482685
2016 Mechanical stretching stimulates collagen synthesis via down-regulating SO2/AAT1 pathway. Scientific reports 24 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 18 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