Ddr (Drosophila melanogaster, Q59DZ7, FBgn0053531) curation notes

2026-11-06 literature search

No deep-research provider was available (no API keys); just deep-research was not run.
FlyBase has no hand-written gene description for Ddr, so no -deep-research-flybase.md
was produced. Searches done by hand:

• PubMed Drosophila discoidin domain receptor Ddr -> 1 hit (PMID:36355066).
• PubMed (Drosophila OR fly OR insect) AND (discoidin domain receptor OR CG33531) -> 10
  hits; apart from PMID:36355066 and PMID:37919278, all are about mammalian DDR1/DDR2
  (some expressed in insect cells) or unrelated.
• PubMed "Ddr"[tiab] AND Drosophila[tiab] -> 39 hits; all others use "DDR" for the DNA
  damage response.
• PubMed Ddr Drosophila (olfactory OR axon OR wound OR basement membrane OR collagen) receptor tyrosine kinase discoidin -> only PMID:36355066.
• Web searches for Ddr in olfactory axon targeting, fasciculation, wound healing and
  basement membrane: only the Corty et al. paper, its bioRxiv preprint and the
  InteractiveFly/FlyBase pages that summarise it.

Leads given to me that I could not verify: a role of fly Ddr in olfactory receptor
neuron axon targeting or fasciculation, and wound or basement-membrane roles. I found no
publication for either. They are not used in the review.

What is known

Glial Ddr in axon ensheathment (Corty et al. 2022, PMID:36355066, full text cached)

• In vivo RNAi screen in peripheral wrapping glia identified Ddr PMID:36355066
• CRISPR null alleles (frameshifts giving ~150-aa peptides) are viable PMID:36355066
• Two isoforms: a short secreted-like 380-aa form and the 1054-aa full-length receptor
  PMID:36355066 Q59DZ7 is the 1054-aa form.
• Loss reduces larval axon ensheathment, rescued by Ddr in wrapping glia PMID:36355066
• Adult wing nerve: ensheathment normal, but axon caliber reduced and long-term neuron
  survival reduced PMID:36355066; caliber reduction in both mutant and glial RNAi
  PMID:36355066
• Genetic interaction with Multiplexin (type XV/XVIII collagen): dominant, double
  heterozygotes PMID:36355066.
  Authors interpret Mp as a candidate ligand only PMID:36355066 No binding or activation assay
  was done; kinase activity of fly Ddr was not tested.
• Ddr acts alongside EGFR and FGFR (Heartless) in ensheathment PMID:36355066.

Tau modifier screen (PMID:37919278, full text cached)

Human DDR2 was prioritised in progressive supranuclear palsy, and RNAi of fly orthologues
modified tau neurotoxicity in a fly eye model (GMR-Gal4). This is a disease-model modifier
result; it says nothing about the normal function of Ddr and is not used for annotation.

Bioinformatics (Ddr-bioinformatics/RESULTS.md)

• Kinase domain: fly Ddr lacks the beta3 lysine (Ala789), catalytic-loop Asn (Ser897) and
  DFG Asp (Ser910); same three losses in D. virilis and Anopheles. Tribolium DDR and
  C. elegans ddr-2 retain all three; the Apis predicted model (A0A7M7MKP6) keeps the catalytic-loop
  Asn and DFG Asp but has Pro674 at the beta3 lysine, and C. elegans ddr-1 keeps only the catalytic-loop Asn (and lacks the HRD Asp). Dipteran Ddr is predicted to be a pseudokinase. This is the
  main finding of the review and drives the kinase-activity decisions.
• DS domain: Trp52/Asp69 of the DDR2 collagen pocket are not conserved in any invertebrate
  DDR (fly His128, Gly146). Insects have no fibrillar collagen; the module already records
  that Drosophila has only Col4a1, viking and Multiplexin.
• UniProt CAUTION for the FA58C ProRule (PRU00081) also flags missing conserved residues
  in the discoidin domain.

Annotation decisions (summary)

• Plasma membrane (IBA, IEA): ACCEPT. Signal peptide + single TM (Phobius 501-525).
• GO:0038062 PTK collagen receptor activity (IBA, PTN002400507): MODIFY to GO:0004888
  transmembrane signaling receptor activity. The PAINT node is sound for vertebrate DDRs,
  but fly Ddr shows lineage-specific loss of catalytic residues and no collagen-pocket
  conservation; receptor function is supported by architecture plus glial genetics.
• GO:0004672 protein kinase activity (IEA): MARK_AS_OVER_ANNOTATED (pseudokinase
  prediction, untested).
• GO:0005524 ATP binding (IEA): UNDECIDED (glycine loop kept; Lys and DFG Asp lost;
  pseudokinases vary in nucleotide binding).
• GO:0005518 collagen binding (IBA): MARK_AS_OVER_ANNOTATED (no binding data; pocket not
  conserved; Mp interaction genetic only).
• GO:0038063 collagen-activated RTK pathway (IEA from MF): MARK_AS_OVER_ANNOTATED.
• GO:0007169 cell surface RTK signaling pathway (IBA): UNDECIDED.
• GO:0043235 signaling receptor complex (IBA): KEEP_AS_NON_CORE.
• GO:0051897 positive regulation of PI3K/AKT (IBA): MARK_AS_OVER_ANNOTATED.
• NEW: GO:0032285 non-myelinated axon ensheathment (IMP, PMID:36355066) - core.
  Participation: Ddr acts in the wrapping glia that perform the ensheathment (rescue in
  wrapping glia). FlyBase uses GO:0008366 for other glial ensheathment genes (bdl,
  wrapper, fray, Nrg; QuickGO 2026-11-06); GO:0032285 is its more specific child and fits
  non-myelinating wrapping glia. GO:0032294 was avoided because its definition names
  Schwann cells.
• NEW: GO:0031133 regulation of axon diameter (IMP) - non-core, non-cell-autonomous.

Open questions

• Is fly Ddr catalytically dead? Does it signal through a kinase-active partner (EGFR,
  Htl) as ErbB3-type pseudokinase receptors do?
• Does Multiplexin (or collagen IV) bind the Ddr DS domain? Which surface?
• What does the short 380-aa extracellular isoform do?

Family-level follow-up (2026-11-11)

• PANTHER tree placement (interpro/panther/PTHR24416/PTHR24416-review.yaml and
  PTHR24416-bioinformatics/RESULTS.md): the catalytic-triad loss is confined to the dipteran
  node PTN002400510 (Drosophila Ddr and Anopheles DDR); the sister Tribolium paralog clade
  keeps the triad in at least one paralog. The DDR2 collagen pocket (Trp52, Asp69) is kept
  only in the vertebrate DDR node PTN007801558. Recommended PAINT actions: an IKR for
  GO:0004714 at PTN002400510, and moving the GO:0038062 and GO:0005518 IBDs from
  PTN002400507 (Eumetazoa) to PTN007801558.
• OpenScientist was run on "Ddr has protein tyrosine kinase collagen receptor activity
  (GO:0038062)" with the local bioinformatics held out
  (Ddr-hypotheses/function-hypothesis-go-0038062/openscientist.md). It concluded
  "Verdict: Supported — retain GO:0038062 (IBA).", but its two decisive premises do not
  hold on the sequence. It reports "a VAIK-type catalytic lysine"; Q59DZ7 contains no
  VA[IV]K motif and no DFG anywhere (the beta3 strand reads VAVA; checked 2026-11-11). It
  calls the KWIRWRS segment the "collagen-contacting RWxxWR loop", but the aligned DDR2
  segment (residues 128-134) is not among the collagen-contact residues of the DDR2
  DS domain-collagen structure (PMID:20004161: Trp52, Thr56, Asp69, Arg105, Glu113, His110,
  Ile112, Asn175), and Q59DZ7 has His128 at the Trp52 position. The run agrees with the
  local analysis that the HRD aspartate is present. The review's actions are unchanged.