DRC2, also known as CCDC65 or NYD-SP28, is a coiled-coil structural protein of the nexin-dynein regulatory complex in motile ciliary axonemes. It works with other scaffold subunits to organize the complex, link neighboring microtubule doublets and coordinate dynein-driven bending. DRC2 is also present along human sperm tails. Its loss disrupts nexin-link architecture and ciliary beating, causing primary ciliary dyskinesia.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003341 cilium movement | NAS PMID:37258679 Axonemal structures reveal mechanoregulatory and disease mec... | ACCEPT | Summary: DRC2 contributes structural support for ciliary bending through the N-DRC. Reason: DRC2 performs structural work in the nexin-dynein regulatory complex that couples adjacent axonemal doublets and coordinates bending. The cited study places DRC2 in human respiratory axonemes and resolves the detailed DRC1–DRC2 scaffold in algae. Human respiratory phenotypes and algal mutation/rescue independently support its role in ciliary movement. This is structural participation, not autonomous ATP-driven motor activity. |
| GO:0003352 regulation of cilium movement | IBA GO_REF:0000033 | ACCEPT | Summary: The conserved N-DRC scaffold regulates ciliary beating. Reason: The literal regulation IBD at PTN000492844 is on the human DRC2 path in PTHR21625, and the target alignment matches the 484-residue reference product. Its human DRC2 and zebrafish donor assertions are grounded in PMID:24094744. Human stiff dyskinetic cilia and altered zebrafish beating support regulation by the N-DRC scaffold. The target appearing among its own descendant evidence is legitimate experimental grounding, not circular support. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000492844 · PTN000492844 SUPPORTS TRANSFER The four literal IBD assertions share PTN000492844. This regulation assertion has exact human Q8IXS2 and ZFIN:ZDB-GENE-030616-358 donor joins; official zebrafish identity maps the latter to Q6DHI2. |
| GO:0003352 regulation of cilium movement | IMP PMID:24094744 Zebrafish Ciliopathy Screen Plus Human Mutational Analysis I... | ACCEPT | Summary: Human CCDC65 variants and zebrafish depletion alter ciliary beating. Reason: Human CCDC65 variants cause stiff dyskinetic respiratory cilia, and zebrafish ccdc65 depletion alters beating. Together with the disrupted nexin links, these observations support regulation of ciliary movement by the N-DRC scaffold. The separately recovered 2013 human Results report reduced inner arms, whereas Figure 6B broadly describes normal arms; outer-arm preservation is consistent across the source. The movement claim rests on the observed waveform, not on resolving that ultrastructural discrepancy. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:34169321 Loss of DRC1 function leads to multiple morphological abnorm... | MODIFY | Summary: DRC2 associates with the axonemal cytoskeletal protein DRC1. Reason: Controlled tagged co-immunoprecipitation supports the curated DRC2–DRC1/Q96MC2 association. The human axonemal structural inventory independently places DRC1 in the N-DRC, a protein component of the microtubule cytoskeleton, which fits the definition of cytoskeletal protein binding. That definition is not restricted to filament polymers or motor proteins. The association assay does not resolve direct contact, and its introduced ORF species and sequence remain unauthenticated in the accessible main text and supplement. Proposed replacements: cytoskeletal protein binding |
| GO:0005858 axonemal dynein complex | IEA GO_REF:0000002 | MODIFY | Summary: DRC2 belongs to the N-DRC rather than the dynein motor complex. Reason: The InterPro family mapping conflates the nexin-dynein regulatory complex with the axonemal dynein motor complex. The current GO:0005858 definition describes the motor complex, whereas human structural placement and conserved DRC2 architecture establish N-DRC membership. Replace it with axonemal nexin link. Participation in assembly or regulation of adjacent dyneins does not make DRC2 a motor subunit. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: InterPro:IPR039750 SOURCE BAD The target match to the actual IPR039750 family is authentic, but its GO:0005858 membership mapping conflates the N-DRC with the distinct dynein motor complex. This source mapping is wrong for the claim; its separate GO:0070286 assembly mapping remains supported. Proposed replacements: axonemal nexin link |
| GO:0005930 axoneme | IBA GO_REF:0000033 | ACCEPT | Summary: Conserved axonemal localization is supported by phylogeny and human structural placement. Reason: Accept the ancestral axoneme assertion: the literal GO:0005930 IBD at PTN000492844 lies on the human DRC2 lineage. Its Q32KY1 and Q384U1 donor identities are preserved, with independent trypanosome CMF70 axonemal localization and human respiratory-axoneme structural placement. Axoneme identifies the supported anatomical location; the separate nexin-link annotation records complex membership. The tagged basal-body observation is an additional source-specific pool. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000492844 · PTN000492844 SUPPORTS TRANSFER The literal axoneme IBD has Q32KY1/Q384U1 descendant evidence and the human Q8IXS2 lineage inherits it. Human structural placement independently corroborates the anatomical location; no source error or loss is inferred. |
| GO:0005930 axoneme | NAS PMID:37258679 Axonemal structures reveal mechanoregulatory and disease mec... | ACCEPT | Summary: Human respiratory-axoneme reconstruction places DRC2 in the axoneme. Reason: The human respiratory-axoneme reconstruction identifies DRC2/Q8IXS2 in Supplementary Table 3 and places homologous N-DRC subcomplexes in cryo-EM density. This supports axonemal location in addition to N-DRC membership. Detailed coiled-coil contacts were resolved principally in algae; the human model placement does not independently establish every atomic interface or an isoform-specific distribution. Supporting Evidence: |
| GO:0005931 axonemal nexin link | NAS PMID:37258679 Axonemal structures reveal mechanoregulatory and disease mec... | ACCEPT | Summary: DRC2 is a component of the axonemal nexin link. Reason: Human Supplementary Table 3 explicitly lists DRC2/Q8IXS2, 484 residues, among N-DRC components, and the respiratory-axoneme model places the homologous complex in density. This directly supports the imported complex membership. Detailed scaffold geometry and the proposed doublet-contact mechanism are resolved principally in algae; the human model does not demonstrate identical atomic contacts or equivalent function of the 497-residue alternative product. |
| GO:0030317 flagellated sperm motility | NAS PMID:37258679 Axonemal structures reveal mechanoregulatory and disease mec... | ACCEPT | Summary: The conserved flagellar scaffold supports the curated sperm-motility context. Reason: Retain the curated sperm-motility assertion as the sperm-tail application of the conserved N-DRC structural mechanism. Endogenous human DRC2 is localized throughout the sperm tail in PMID:17089017; phylogenetic and algal functional evidence support the inherited flagellar mechanism. PMID:37258679 examines respiratory cilia and algae, so it corroborates the scaffold rather than a human sperm perturbation. Neither the localization assay nor the capacitation-associated gel shift by itself demonstrates a sperm-specific causal mechanism. Supporting Evidence: PMID:17089017 immunoreactivity was detected in entire sperm tail. |
| GO:0031514 motile cilium | IEA GO_REF:0000044 | ACCEPT | Summary: Respiratory-ciliary and sperm-tail evidence supports motile-cilium localization. Reason: Accept motile-cilium localization. Human respiratory-axoneme structural placement and endogenous sperm-tail localization independently support the anatomical context represented by the UniProt flagellum mapping. The curated location record includes by-similarity provenance, which is distinct from those human observations. N-DRC membership supplies complementary complex information and does not replace the motile-cilium location; the tagged basal-body pool remains separately retained. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0117 SUPPORTS TRANSFER The actual SL-0117 vocabulary record maps flagellum to motile cilium. Human respiratory-ciliary and sperm-tail evidence supports this anatomical scope independently of the by-similarity record. |
| GO:0036064 ciliary basal body | IDA PMID:29257953 Evolutionary Proteomics Uncovers Ancient Associations of Cil... | KEEP AS NON CORE | Summary: A tagged human DRC2 construct has a secondary basal-body localization. Reason: Figure 3C directly shows GFP-tagged human CCDC65/DRC2 at the ciliary base of IMCD3 cells with CEP164 and ciliary tubulin markers. The Methods specify human cDNA fusions. This positive source-specific basal-body observation is retained as a secondary localization alongside the mature axonemal N-DRC pool. It is not an endogenous human tissue assay, does not authenticate the natural isoform of the introduced insert, and does not by itself establish a separate basal-body mechanism. Supporting Evidence: |
| GO:0060271 cilium assembly | IMP PMID:24094744 Zebrafish Ciliopathy Screen Plus Human Mutational Analysis I... | MODIFY | Summary: DRC2 supplies structural work in assembly and organization of the axoneme. Reason: Refine cilium assembly to axoneme assembly because DRC2 supplies an N-DRC scaffold that organizes associated axonemal components. In the original algal experiments, the FAP250/DRC2 mutation disrupts N-DRC and closely associated inner-arm assembly; genomic rescue restores these structures and protein incorporation (PMID:24094744, Figure 6H–J and the FAP250 Results section). Human respiratory-axoneme modeling independently places DRC2 in this structural system (PMID:37258679). The 2013 human Results/caption differ about inner arms, and the 2023 study leaves human IDAe docking dependence unresolved. The refinement therefore rests on conserved structural participation, not universal human arm loss or failure to form a ciliary projection. Proposed replacements: axoneme assembly |
| GO:0060285 cilium-dependent cell motility | IBA GO_REF:0000033 | MODIFY | Summary: Sperm flagellar motility is the supported human context of the inherited cell-motility function. Reason: The literal GO:0060285 IBD at PTN000492844 and human target descent support an inherited flagellar cell-motility role. Human sperm-tail localization and the conserved N-DRC scaffold identify flagellated sperm motility as the relevant human specialization; respiratory cilia instead move material across a cell surface. This is the same structural mechanism underlying the accepted sperm-motility row, with human localization and ortholog functional evidence kept distinct. The sources do not establish a new human sperm perturbation or a causal capacitation mechanism. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000492844 · PTN000492844 SUPPORTS TRANSFER Exact donors MGI:MGI:2685906, Q384U1, Q96MC2 and Q32KY1 join the literal GO:0060285 IBD. MGI:2685906 maps to mouse DRC1/Q3USS3; its current matching records are propagated, which does not establish circularity or invalidate the historical PAINT judgment. GO:0030317 is a verified descendant of GO:0060285. Proposed replacements: flagellated sperm motility |
| GO:0070286 axonemal dynein complex assembly | IBA GO_REF:0000033 | ACCEPT | Summary: Conserved N-DRC structure contributes to assembly of associated inner dynein arms. Reason: The literal GO:0070286 IBD and human descent support conserved assembly participation, with the Q32KY1/Q96MC2 donor identities retained. Independent algal DRC2 mutation and genomic rescue establish assembly of the N-DRC and closely associated inner dynein arms (PMID:24094744, Figure 6H–J). PMID:37258679 explicitly distinguishes algal IDAe dependence from unresolved human IDAe docking dependence. This supports a conserved structural contribution without assigning a particular human dynein subtype; the differing human inner-arm Results and Figure 6B caption remain a separately documented source limitation. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000492844 · PTN000492844 SUPPORTS TRANSFER The GO:0070286 IBD is at PTN000492844 with exact Q32KY1/Q96MC2 donor joins and human Q8IXS2 target descent. The DRC2-specific original supports conserved selective assembly participation; absence of a directly measured human IDAe dependency is not evidence of target-lineage loss. |
| GO:0070286 axonemal dynein complex assembly | IEA GO_REF:0000002 | ACCEPT | Summary: The family assembly mapping is supported by DRC2 mutation and rescue evidence. Reason: The InterPro assembly mapping is supported by the DRC2-specific algal mutation/rescue experiments and the conserved N-DRC scaffold. FAP250/DRC2 rescue restores associated inner-arm structure and axonemal incorporation in PMID:24094744, Figure 6H–J; PMID:37258679 reports algal IDAe loss while leaving human IDAe docking dependence open. Assembly participation is therefore retained even though the separate motor-complex membership mapping is incorrect. The human Results/caption discrepancy is not used as decisive evidence for a human arm subtype. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR039750 SUPPORTS TRANSFER The actual IPR039750 family description and GO:0070286 mapping agree with independently inspected DRC2 scaffold and selective assembly evidence; no autonomous motor function is inferred. |
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Download this section (compressed HTML)Q: Which human inner-arm dynein subtypes depend on DRC2-containing N-DRC for stable docking, given preserved outer arms and the differing inner-arm descriptions in the 2013 source?
Q: Does the 497-residue alternative C terminus change DRC2 complex incorporation or its basal-body and mature-axoneme pools?
Q: What modification causes the human sperm capacitation-associated DRC2 gel shift, and does changing it alter flagellar waveform?
Q: Does the tagged basal-body pool represent a native assembly intermediate, a persistent secondary localization, or a construct-dependent pool?
Experiment: Compare isogenic human airway cultures carrying a DRC2 loss-of-function allele and sequence-verified rescue. Quantify specific inner-arm subunits and N-DRC architecture by cryo-electron tomography or resolved immunolocalization alongside outer-arm controls and ciliary waveform measurements.
Hypothesis: Human DRC2 supports selective inner-arm docking through its structural N-DRC role.
Type: Human structural rescue and motility analysis
Experiment: Express sequence-authenticated 484- and 497-residue products at matched levels in a DRC2-deficient background, measuring N-DRC incorporation and endogenous-marker-resolved basal-body versus axonemal localization. Keep the two documented early-clone substitutions separate from the natural-product comparison.
Hypothesis: The alternative C terminus alters recruitment or localization without necessarily abolishing assembly.
Type: Isoform-resolved rescue and localization
Experiment: Identify DRC2 modifications before and after human sperm capacitation by targeted mass spectrometry, then test candidate modifications in an appropriate sequence-verified functional system before assigning a causal capacitation role.
Type: Modification mapping and functional testing
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