A0A2K5UJ34

UniProt ID: A0A2K5UJ34
Organism: Macaca fascicularis
Review Status: COMPLETE
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Gene Description

Tetratricopeptide repeat protein 39C (TTC39C) from Macaca fascicularis (crab-eating macaque). TTC39C is a member of the TTC39 protein family and contains TPR (tetratricopeptide repeat) domains (IML2/TPR_39, IPR019412) that fold into helix-turn-helix superhelical structures mediating protein-protein interactions. The protein is predicted to function as a non-catalytic scaffold or adaptor protein, consistent with the general role of TPR domain proteins in organizing multi-protein complexes. TTC39C has been experimentally shown to localize to cilia in C. elegans sensory neurons (Pir et al. 2024, Ciliogenics study), suggesting a role in ciliary biology. The zebrafish ortholog (Q1LXE6) has experimental evidence (IMP) for involvement in determination of heart left/right asymmetry, a cilium-dependent process in vertebrate development, and for otolith morphogenesis. The better-characterized paralog TTC39B functions as a scaffold promoting ubiquitination and proteasomal degradation of liver X receptor alpha (LXRalpha), thereby regulating cholesterol homeostasis, but whether TTC39C shares this specific regulatory role is unknown. This is an unreviewed TrEMBL entry (545 aa, chromosome 18) with no direct experimental studies on the macaque protein; all functional inference comes from orthologs and domain architecture.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0032474 otolith morphogenesis
IEA
GO_REF:0000118 		MARK AS OVER ANNOTATED
Summary: Otolith morphogenesis (GO:0032474) refers to the generation and organization of otoliths, which are calcium carbonate structures in the inner ear of fish and some aquatic vertebrates used for balance and hearing. Mammals, including Macaca fascicularis, do not possess otoliths; they have otoconia instead. This annotation was transferred by TreeGrafter from the zebrafish ortholog TTC39C, which has experimental evidence (IMP) for involvement in otolith morphogenesis. While the underlying biology (inner ear vestibular structure formation) may be partially conserved across vertebrates, the specific GO term GO:0032474 is taxonomically inappropriate for a primate. The mammalian equivalent process would be related to otoconium formation or inner ear development, but those are distinct biological structures. This is a clear case of over-annotation resulting from automated cross-species transfer of a taxon-specific process term.
Reason: Otoliths are fish-specific structures. Macaques have otoconia, not otoliths. The TreeGrafter transfer from zebrafish propagated a taxon-inappropriate term. While the gene may be involved in inner ear development in mammals, this specific term should not be applied to a primate protein.
GO:0060271 cilium assembly
IEA
GO_REF:0000118 		ACCEPT
Summary: Cilium assembly (GO:0060271) describes the formation of a cilium, including the centriole-to-basal body transition, basal body docking, and axoneme extension. This annotation was transferred by TreeGrafter and is well-supported by multiple lines of evidence. First, TTC39C was experimentally confirmed to localize to cilia of sensory neurons in C. elegans (amphid and phasmid cilia) by Pir et al. 2024 in the Ciliogenics study. Second, the zebrafish ortholog has experimental evidence for cilium-dependent processes (heart left/right asymmetry determination, otolith morphogenesis -- both require functional cilia). Third, TPR domain proteins are well-established scaffolds in ciliary biology, with many TPR-containing proteins functioning in intraflagellar transport and ciliogenesis. The TreeGrafter transfer from the PANTHER family (PTN001275231) appropriately captures TTC39C's likely involvement in ciliary biology, a process that is highly conserved across vertebrates and metazoans.
Reason: Cilium assembly is a conserved process across metazoans. TTC39C ciliary localization has been experimentally validated in C. elegans, the zebrafish ortholog has IMP evidence for cilium-dependent developmental processes, and TPR domain proteins commonly function as ciliary scaffolds. The IEA TreeGrafter transfer is appropriate.

Core Functions

TTC39C is predicted to function as a TPR-domain adaptor protein at cilia, likely involved in organizing protein complexes required for cilium assembly and possibly ciliary signaling. The protein lacks catalytic domains and its TPR repeats mediate protein-protein interactions. Ciliary localization has been experimentally validated for the C. elegans ortholog, and the zebrafish ortholog has IMP evidence for cilium-dependent developmental processes (heart laterality determination).

Molecular Function:
protein-macromolecule adaptor activity
Directly Involved In:
cilium assembly
Cellular Locations:
cilium
Supporting Evidence:
  • file:MACFA/A0A2K5UJ34/A0A2K5UJ34-deep-research-falcon.md
    [Pir et al. 2024] experimental validation confirmed that both TTC39A/C and TMEM145 localize to the cilia of sensory neurons in both the head (amphid) and tail (phasmid) regions of C. elegans

References

GO_REF:0000118
TreeGrafter-generated GO annotations
file:MACFA/A0A2K5UJ34/A0A2K5UJ34-deep-research-falcon.md
Deep research report on TTC39C in Macaca fascicularis

External Prediction Reviews

These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.

ProtNLM2 External predictions

View prediction review YAML · A0A2K5UJ34-protnlm-predictions-review.yaml · Review status: COMPLETE

TTC39C subfamily placement supports a family-based inference of a role in vertebrate heart left-right patterning through cilia.

Source documents: genes/MACFA/A0A2K5UJ34/A0A2K5UJ34-uniprot.txt · genes/MACFA/A0A2K5UJ34/A0A2K5UJ34-goa.tsv · publications/PMID_25860617.md

Review score: 2 = concordant with evidence; 1 = uncertain; 0 = discordant with evidence. This is an assessment score, not a model probability.

GO:0061371 determination of heart left/right asymmetry GO_BP
COR — Correct novel prediction Review score: 2/2
Prediction method: ProtNLM2 · Version: UniProt 2024_06 pilot
Review rationale: The target is assigned specifically to the TTC39C subfamily rather than only to a generic TPR-repeat fold. Zebrafish ttc39c perturbation in a primary cilia study produced laterality defects, including abnormal heart positioning (PMID:25860617). Conservation of the TTC39C ciliary role and vertebrate cilia-dependent laterality provides a reasonable basis for transferring the broad heart-asymmetry process to macaque TTC39C. This is an ortholog-based inference rather than a macaque experiment; the process is absent from the cached target annotations.
Supporting Evidence:

Deep Research

Falcon

(A0A2K5UJ34-deep-research-falcon.md)

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