DNAAF3

UniProt ID: Q8N9W5
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

DNAAF3 is a cytoplasmic dynein assembly factor required for maturation of outer and inner dynein arms before their deployment in motile cilia. Deficiency disrupts respiratory ciliary beating and can alter left–right organ patterning, causing primary ciliary dyskinesia. The conserved protein concentrates in dynein assembly particles in multiciliated cells. Ortholog genetics, dynein mass spectrometry and structural comparisons support a candidate role in arginine methylation during dynein maturation; intrinsic human methyltransferase activity and its separation from noncatalytic assembly functions remain unresolved. Alternative transcripts encode five predicted products with distinct sequence boundaries.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005737 cytoplasm
IEA
GO_REF:0000044
ACCEPT
Summary: Cytoplasmic assembly factor with enrichment in DynAPs.
Reason: The official SL-0086 assertion maps exactly to cytoplasm. DNAAF3 acts before axonemal deployment of dynein motors, and the Xenopus DNAAF3 fusion in PMID:30561330 Figure 2C occupies cytoplasmic foci with a surrounding cytoplasmic pool. Retain the general cytoplasmic location alongside the specifically supported DynAP enrichment; neither assertion makes DNAAF3 a mature axonemal motor.
Propagation Review
Root cause: NO FAILURE CORE
Sources checked:
UniProtKB-SubCell:SL-0086 SUPPORTS TRANSFER
Exact SL-0086 to GO:0005737 mapping verified. Conserved preassembly and Xenopus localization support the cytoplasmic compartment.
Supporting Evidence:
GO_REF:0000044
file:human/DNAAF3/DNAAF3-evidence-guide.md
GO:0044458 motile cilium assembly
IBA
GO_REF:0000033
ACCEPT
Summary: Inherited participation in motile-cilium assembly through maturation of its dynein-arm components.
Reason: The human leaf PTN002502984 descends from PTN001858482 in PTHR22118, and the literal IBD grounding includes genuine human experimental evidence. DNAAF3 promotes maturation of the outer and inner dynein arms that form part of a functional motile cilium. Human patient cilia lack these arms, while ortholog rescue and biochemical experiments identify a cytoplasmic assembly defect: abnormal heavy/intermediate-chain complexes form but fail to become assembly competent. Persistent ciliary projections therefore do not negate participation in their constituent assembly. This is a core role. GO:0036158 and GO:0036159 are not current is_a/part_of descendants of GO:0044458, so those separately represented arm-assembly processes do not replace this inherited claim.
Propagation Review
Root cause: NO FAILURE CORE
Sources checked:
PANTHER:PTN001858482 SUPPORTS TRANSFER
Valid root-to-human descent and both IBD annotations verified. The saved IBD snapshot contains fly and human seeds, while current QuickGO also lists zebrafish; no donor-count objection or target circularity is inferred.
Supporting Evidence:
GO_REF:0000033
file:human/DNAAF3/DNAAF3-evidence-guide.md
GO:0044458 motile cilium assembly
IMP
PMID:22387996
Mutations in axonemal dynein assembly factor DNAAF3 cause pr...
ACCEPT
Summary: DNAAF3 contributes to assembly of functional motile cilia by maturing their axonemal dynein arms.
Reason: PMID:22387996 directly shows loss of both dynein-arm classes in human patient respiratory cilia; zebrafish knockdown leaves ciliary morphology and number largely intact while disrupting arms and motility. In Chlamydomonas, rescue and cytoplasmic heavy/intermediate-chain assays show that PF22/DNAAF3 supports maturation into assembly-competent motors. The performed work is dynein-component assembly, not merely an effect on beating or a claim that DNAAF3 builds the ciliary membrane. GO:0044458 encompasses arrangement of components into a motile cilium, making this core participation despite persistence of projections. The specific arm terms are retained separately because neither is an is_a/part_of descendant of GO:0044458.
Supporting Evidence:
PMID:22387996
cilia that lack both outer and inner dynein arms
file:human/DNAAF3/DNAAF3-evidence-guide.md
GO:0070286 axonemal dynein complex assembly
IBA
GO_REF:0000033
MODIFY
Summary: Inherited axonemal dynein assembly includes both outer and inner arms.
Reason: PTHR22118 places the human target beneath the stated PTN001858482 ancestral node, whose GO:0070286 IBD is experimentally grounded. Refine the broader assembly term to its verified outer-arm and inner-arm assembly children using the target-specific evidence in PMID:22387996. This preserves the positive phylogenetic judgment and does not infer catalytic motor activity.
Propagation Review
Root cause: TERM SCOPING PROBLEM
Failure modes: GRANULARITY MISMATCH
Sources checked:
PANTHER:PTN001858482 SUPPORTS TRANSFER
Node placement, current GO:0070286 annotation and human target descent are verified; the change supplies target-level specificity rather than rejecting inheritance.
Supporting Evidence:
GO_REF:0000033
file:human/DNAAF3/DNAAF3-evidence-guide.md
GO:0070286 axonemal dynein complex assembly
IEA
GO_REF:0000002
MODIFY
Summary: Correct family mapping can be refined to outer and inner dynein-arm assembly.
Reason: IPR039304 is the DNAAF3 family, with an actual human target match over canonical residues 1–470 and an explicit GO:0070286 mapping. The InterPro entry cites PMID:22387996 and describes preassembly of both inner and outer arms. Refine the correct broad mapping to those two specific assembly processes without assigning an independent chaperone or motor activity.
Propagation Review
Root cause: TERM SCOPING PROBLEM
Failure modes: GRANULARITY MISMATCH
Sources checked:
InterPro:IPR039304 SUPPORTS TRANSFER
Official family, target match and exact InterPro2GO mapping verified. Source biology supports both proposed child processes.
Supporting Evidence:
GO_REF:0000002
file:human/DNAAF3/DNAAF3-evidence-guide.md
GO:0070286 axonemal dynein complex assembly
IMP
PMID:22387996
Mutations in axonemal dynein assembly factor DNAAF3 cause pr...
MODIFY
Summary: Experimental assembly phenotype resolved to outer and inner dynein arms.
Reason: The human and ortholog findings in PMID:22387996 support DNAAF3-dependent dynein-arm preassembly. Outer dynein arm assembly and inner dynein arm assembly are verified is_a children of the existing term and express the two supported target-level components. Preserve the original experimental assertion while making its biological scope more specific.
Supporting Evidence:
PMID:22387996
Its loss prevents correct assembly of inner and outer dynein arms
file:human/DNAAF3/DNAAF3-evidence-guide.md
GO:0120293 dynein axonemal particle
IEA
GO_REF:0000044
ACCEPT
Summary: DynAP localization from a correctly mapped, experimentally grounded ortholog inference.
Reason: SL-0542 maps exactly to dynein axonemal particle. The human UniProt location traces to Xenopus laevis DNAAF3 Q32NQ7, whose direct IDA evidence is PMID:30561330. The original Figure 2C shows tagged Xenopus DNAAF3 co-localizing with Ktu in cytoplasmic DynAPs. Retain the conserved location, while distinguishing it from direct imaging of endogenous human DNAAF3 or demonstrated localization of every predicted human isoform.
Propagation Review
Root cause: NO FAILURE CORE
Sources checked:
UniProtKB-SubCell:SL-0542 SUPPORTS TRANSFER
Exact mapping to GO:0120293 verified; human UniProt explicitly cites the experimentally localized Xenopus Q32NQ7 donor.
Supporting Evidence:
GO_REF:0000044
file:human/DNAAF3/DNAAF3-evidence-guide.md
GO:0120293 dynein axonemal particle
ISS
GO_REF:0000024
ACCEPT
Summary: Experimentally localized Xenopus ortholog supports the human DynAP transfer.
Reason: The literal donor Q32NQ7 is Xenopus laevis dnaaf3 and carries direct IDA to GO:0120293 from PMID:30561330. Methods identify DNAAF3 cloned from a Xenopus cDNA library, and Figure 2C shows the DNAAF3 fluorescent fusion in Ktu-positive DynAPs. This positive source evidence supports the curator's ortholog transfer. Human staining in the same paper assays LRRC6 and DNAI1, so it is not presented as direct human DNAAF3 imaging.
Propagation Review
Root cause: NO FAILURE CORE
Sources checked:
UniProtKB:Q32NQ7 SUPPORTS TRANSFER
Verified Xenopus DNAAF3 with direct IDA30561330 localization. Its separate assembly ISS to human does not make this independently measured localization circular.
Supporting Evidence:
PMID:30561330
all tested DNAAFs co-localized significantly in cytosolic foci
GO_REF:0000024
file:human/DNAAF3/DNAAF3-evidence-guide.md

Core Functions

Promotes cytoplasmic maturation of assembly-competent outer and inner axonemal dynein arms, contributing these components to motile-cilium assembly, with conserved enrichment in DynAPs. Human arm defects and ortholog complementation/complex assays support the assembly role. DNAAF3/PF22 is a candidate arginine methyltransferase, supported by structural comparisons and loss of dynein arginine methylation in an algal null mutant; the intrinsic catalytic activity and its causal relationship to maturation remain unresolved.

Supporting Evidence:

References

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Suggested Questions for Experts

Q: Which natural DNAAF3 protein products are expressed in human multiciliated cells, and do they share assembly activity and DynAP localization?

πŸ“š Additional Documentation

Notes

(DNAAF3-notes.md)

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Evidence Guide

(DNAAF3-evidence-guide.md)

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