Affinage

Showing DNAAF19 — CCDC103 is a alias.

DNAAF19

Dynein axonemal assembly factor 19 · UniProt Q8IW40

Length
242 aa
Mass
27.2 kDa
Annotated
2026-06-09
21 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DNAAF19 (CCDC103) is an axoneme-associated assembly factor required for docking of outer dynein arms onto ciliary axonemes, and loss-of-function disrupts ciliary motility in primary ciliary dyskinesia (PMID:22581229). It integrates tightly along the entire length of the axoneme independently of other dynein or docking-complex subunits and binds microtubules directly, decorating the lattice with ~12-nm periodicity that matches the outer-arm dynein repeat (PMID:25572396). The protein self-associates into dimers and higher-order oligomers through two distinct interfaces, a disordered N-terminal segment and the C-terminal RPAP3_C domain, generating the molecular scaffold needed for dynein-arm attachment (PMID:25572396, PMID:31858719). CCDC103 functions as an adaptor coupling chaperone machinery to dynein assembly: it binds the RUVBL1-RUVBL2 AAA+ ATPase ring through a dedicated RUVBL2-binding domain, forming a hetero-hexameric ring bound to three CCDC103 molecules (the R2C complex), with its flexible N-terminus regulating RUVBL1-RUVBL2 oligomerisation [PMID:bio_10.1101_2025.09.11.675549]. Beyond cilia, CCDC103 colocalizes with cytoplasmic microtubules in myeloid cells and stabilizes them through a direct interaction with SPAG6, supporting myeloid cell proliferation and directed migration (PMID:34028558). Pathogenic PCD variants act mechanistically by disrupting oligomerisation (e.g. p.His154Pro in the RPAP3_C domain) and by abrogating the SPAG6 interaction (PMID:28790179, PMID:31858719, PMID:34028558).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2012 High

    Established that CCDC103 is required for outer dynein arm assembly, defining it as a ciliary dynein attachment factor whose mutation causes motility defects.

    Evidence Zebrafish genetic rescue with wild-type vs. mutant CCDC103, Chlamydomonas axoneme biochemistry, and EM of dynein arm defects

    PMID:22581229

    Open questions at the time
    • Molecular mechanism of how it attaches dynein arms not resolved
    • No structural basis for axoneme integration
  2. 2015 High

    Showed how CCDC103 is built into the axoneme: it integrates independently of other components, oligomerises, and binds microtubules with a periodicity matching the dynein repeat, providing a physical scaffolding model.

    Evidence Axoneme extraction assays, dynamic light scattering, in vitro microtubule binding, and EM of MT-CCDC103 complexes

    PMID:25572396

    Open questions at the time
    • Direct contacts with dynein motor not mapped
    • Stoichiometry to dynein inferred from periodicity, not co-reconstitution
  3. 2017 Medium

    Provided a molecular explanation for a PCD allele by showing the p.His154Pro variant disrupts oligomerisation.

    Evidence In vitro oligomerisation assay on purified mutant vs. wild-type protein

    PMID:28790179

    Open questions at the time
    • Single method, single lab
    • Did not test effect on dynein docking directly
  4. 2019 Medium

    Resolved the architecture of self-association, identifying two distinct interfaces (disordered N-terminus and RPAP3_C domain) and localizing the H154P pathogenic mutation to RPAP3_C.

    Evidence Biochemical self-interaction assays with domain truncations and molecular modeling of RPAP3_C

    PMID:31858719

    Open questions at the time
    • Structural model of RPAP3_C not experimentally determined
    • Functional consequence of each interface for dynein assembly untested
  5. 2021 High

    Extended CCDC103 function beyond cilia, showing a cilia-independent role in stabilizing cytoplasmic microtubules and supporting myeloid cell proliferation and migration via a direct SPAG6 interaction.

    Evidence Zebrafish ccdc103/smh and spag6 mutant analysis, live imaging, colocalization, and Co-IP of CCDC103 with SPAG6 with PCD-variant controls

    PMID:34028558

    Open questions at the time
    • Mechanism by which SPAG6 binding stabilizes microtubules unclear
    • Reciprocal validation of the interaction not detailed
  6. 2025 High

    Defined CCDC103 as a chaperone adaptor by solving the structure of its complex with RUVBL1-RUVBL2 (R2C), linking it to HSP90-based dynein assembly machinery.

    Evidence Cryo-EM at 3.2 Å of the human RUVBL1-RUVBL2-CCDC103 complex with mass spectrometry and biochemical validation (preprint)

    PMID:bio_10.1101_2025.09.11.675549

    Open questions at the time
    • Functional role of R2C in dynein assembly not demonstrated in vivo
    • Preprint, single lab
    • How RUVBL recruitment couples to axonemal docking unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CCDC103's microtubule scaffolding, RUVBL1-RUVBL2 chaperone adaptor activity, and SPAG6-mediated cytoplasmic microtubule stabilization are mechanistically integrated into a single dynein-assembly pathway remains open.
  • No integrated model connecting cytoplasmic chaperone-assisted assembly to axonemal docking
  • Direct CCDC103-dynein contacts uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0060090 molecular adaptor activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005929 cilium 2 GO:0005829 cytosol 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-392499 Metabolism of proteins 1
Partners
RUVBL1RUVBL2SPAG6
Complex memberships
R2C (RUVBL1-RUVBL2-CCDC103)

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 CCDC103 (DNAAF19) encodes a coiled-coil domain protein required for outer dynein arm assembly on ciliary axonemes; it functions as a dynein arm attachment factor. Wild-type but not mutant human CCDC103 rescued dynein arm assembly in zebrafish smh mutants. Chlamydomonas Ccdc103/Pr46b functions as a tightly bound, axoneme-associated protein. Zebrafish genetic rescue (wild-type vs. mutant CCDC103 injection into smh mutants), Chlamydomonas axoneme biochemistry, transmission electron microscopy of dynein arm defects Nature genetics High 22581229
2015 CCDC103 is tightly integrated within the ciliary axoneme along its entire length and does not require other dynein or docking complex components for its integration. It is not solubilized by 0.6 M NaCl but requires 0.5 M KI or 0.3% sarkosyl. CCDC103 forms stable dimers and higher-order oligomers through interactions involving its central RPAP3_C domain. It binds microtubules directly, forming ~9-nm diameter particles with ~12-nm spacing on the microtubule lattice, suggesting two CCDC103 units per outer arm dynein repeat. Axoneme fractionation/extraction assays, dynamic light scattering, in vitro microtubule binding assay, electron microscopy of microtubule-CCDC103 complexes The Journal of biological chemistry High 25572396
2017 The CCDC103 p.His154Pro missense variant disrupts protein oligomerisation, as demonstrated by oligomerisation assay, providing a molecular mechanism for its pathogenicity in PCD. Oligomerisation assay on purified CCDC103 p.His154Pro vs. wild-type protein Thorax Medium 28790179
2019 CCDC103 forms molecular scaffolds through two distinct self-interaction regions: (1) a 27-residue intrinsically disordered N-terminal segment that mediates heat/detergent-resistant dimerization, and (2) the C-terminal RPAP3_C alpha-helical domain. These associations are stable to heating with detergent and are not disrupted by reducing agents. The pathogenic H154P mutation is located within the RPAP3_C domain; molecular modeling showed structural consequences of this substitution. Biochemical self-interaction assays (heat/detergent resistance, domain truncations fused to unrelated monomeric proteins), molecular modeling of RPAP3_C domain Cytoskeleton (Hoboken, N.J.) Medium 31858719
2021 CCDC103 is required for proliferation and directed migration of myeloid cells independently of motile cilia. In zebrafish ccdc103/smh mutants, macrophages and neutrophils show reduced proliferation, abnormally rounded morphology, and impaired migration to sterile wounds, consistent with loss of cytoplasmic microtubule stability. CCDC103 colocalizes with cytoplasmic microtubules in human myeloid cells. CCDC103 directly interacts with SPAG6 (which promotes microtubule stability), and this interaction is abrogated by PCD patient-derived CCDC103 mutations. spag6 zebrafish mutants recapitulate the myeloid defects of smh mutants. Zebrafish genetic mutant analysis (smh/ccdc103 and spag6 mutants), live imaging of myeloid cell migration and morphology, immunofluorescence colocalization, co-immunoprecipitation/interaction assay of CCDC103 with SPAG6, mutagenesis with PCD patient variants Disease models & mechanisms High 34028558
2025 CCDC103 directly binds the RUVBL1-RUVBL2 AAA+ ATPase complex (R2TP-related machinery) via a defined RUVBL2-binding domain (RBD), forming a hetero-hexameric RUVBL1-RUVBL2 ring bound to three CCDC103 molecules — a complex termed R2C. Unlike RPAP3 of the canonical R2TP co-chaperone, CCDC103 lacks a PIH1D1-binding motif and TPR domains. The flexible N-terminal region of CCDC103 regulates RUVBL1-RUVBL2 oligomerisation. This positions CCDC103 as an adaptor linking HSP90/RUVBL1-RUVBL2 chaperone machinery to axonemal dynein motor assembly. Cryo-electron microscopy structure at 3.2 Å resolution of the human RUVBL1-RUVBL2-CCDC103 complex, mass spectrometry (Roumeliotis/Choudhary), biochemical characterization bioRxivpreprint High bio_10.1101_2025.09.11.675549

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 CCDC103 mutations cause primary ciliary dyskinesia by disrupting assembly of ciliary dynein arms. Nature genetics 191 22581229
2017 Quantitative Proteomic Analysis of Human Airway Cilia Identifies Previously Uncharacterized Proteins of High Abundance. Journal of proteome research 69 28282151
2017 High prevalence of CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations. Thorax 69 28790179
2019 Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort. Journal of medical genetics 66 31879361
2015 The oligomeric outer dynein arm assembly factor CCDC103 is tightly integrated within the ciliary axoneme and exhibits periodic binding to microtubules. The Journal of biological chemistry 36 25572396
2015 Mutation analysis in patients with total sperm immotility. Journal of assisted reproduction and genetics 34 25877373
2022 A recurrent homozygous missense mutation in CCDC103 causes asthenoteratozoospermia due to disorganized dynein arms. Asian journal of andrology 17 35259782
2015 A case report of primary ciliary dyskinesia, laterality defects and developmental delay caused by the co-existence of a single gene and chromosome disorder. BMC medical genetics 15 26123568
2019 Differential coexpression networks in bronchiolitis and emphysema phenotypes reveal heterogeneous mechanisms of chronic obstructive pulmonary disease. Journal of cellular and molecular medicine 13 31419013
2020 Situs inversus totalis and prenatal diagnosis of a primary ciliary dyskinesia. Journal of clinical ultrasound : JCU 10 32447765
2021 A simultaneous next-generation sequencing approach to the diagnosis of couple infertility. Minerva endocrinology 9 33988008
2024 Genetics of 67 patients of suspected primary ciliary dyskinesia from India. Clinical genetics 7 39004944
2023 Pulmonary radioaerosol mucociliary clearance assessment: searching for genotype-specific differences and potential as an outcome measure in primary ciliary dyskinesia. ERJ open research 7 38076675
2023 Genetic Analysis of Patients with Congenital Hypogonadotropic Hypogonadism: A Case Series. International journal of molecular sciences 6 37108593
2019 The outer dynein arm assembly factor CCDC103 forms molecular scaffolds through multiple self-interaction sites. Cytoskeleton (Hoboken, N.J.) 6 31858719
2024 Characterization of pathogenic genetic variants in Russian patients with primary ciliary dyskinesia using gene panel sequencing and transcript analysis. Orphanet journal of rare diseases 5 39180133
2021 Ccdc103 promotes myeloid cell proliferation and migration independent of motile cilia. Disease models & mechanisms 4 34028558
2023 Case report: The CCDC103 variant causes ultrastructural sperm axonemal defects and total sperm immotility in a professional athlete without primary ciliary diskinesia. Frontiers in genetics 3 36777727
2026 Two Distinct Clinical Presentations of Primary Ciliary Dyskinesia (PCD): Diagnostic Utility of Whole-Exome Sequencing in a Genetically Heterogeneous Disorder. The application of clinical genetics 0 41948467
2025 Evaluation of the Clinical and Genetic Characteristics of Primary Ciliary Dyskinesia Patients With Situs Inversus Totalis. Birth defects research 0 39902670
2025 NSUN7 Regulates Sperm Flagella Formation at All Stages of Spermiogenesis. International journal of molecular sciences 0 41516134

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