neur (Neuralized, P29503) — curation notes

Drosophila melanogaster, FBgn0002932, CG11988. 754 aa (isoform 1). Domains: two NHR
(neuralized homology repeat) domains (NHR1 ~106-260, NHR2 ~368-523), C-terminal RING
(C3HC4) zinc finger (701-742). PANTHER PTHR12429 (NEURALIZED), subfamily PTHR12429:SF6
(PROTEIN NEURALIZED).

Role in Notch signalling: ligand E3 ubiquitin ligase (signal-sending cell)

• RING-type E3 ligase: PMID:11740940; PMID:11696324.
• Substrate Delta; promotes its endocytosis/degradation: PMID:11740940
• Also Serrate: PMID:16093323
• Redundancy with Mib1: PMID:16093323; Neur and Mib1 are
  structurally unrelated with similar activities but distinct developmental domains
  PMID:15760269
• Docking: NHR1 binds Dl PMID:17065551; the Dl ICD NXXN motif mediates binding and endocytosis
  PMID:19580805.
• Distinct docking/lysine preferences from Mib1; ubiquitylation of the Dl ICD correlates with
  signalling PMID:22162135; product is multi/poly-ubiquitylated
  PMID:22162135.
• Ubiquitylation-independent Dl activation by Neur in some lateral inhibition contexts
  PMID:28960177
• Membrane targeting via phosphoinositide-binding motif, required downstream of
  ubiquitination for Dl endocytosis PMID:18061562.

Regulation

• Bearded-family proteins (Brd, Tom, E(spl)-C BFMs, Ocho etc.) bind Neur via NXXN motifs and
  compete with Dl, inhibiting Neur in non-SOP cells [PMID:16459303; PMID:19580805].
• Asymmetric segregation to pIIb PMID:12852858.

Other substrates / roles

• Stardust isoforms (NBM-containing) -> Crumbs endocytosis PMID:28400441.
• Long-term memory in MB alpha/beta neurons PMID:18794519 (mechanism undefined).

Pathway-variant relevant biology

• Neur is restricted largely to neural precursors (SOPs) and a few other contexts;
  Mib1 is the broadly-used ligand E3. Two structurally unrelated ligand E3s is a conserved
  metazoan feature (vertebrates have NEURL1/1B and MIB1/2). Neur-specific
  antagonism by Bearded-family proteins is an insect/crustacean feature PMID:19580805.

Annotation decisions

• REMOVE: GO:0005634 nucleus (IEA from UniProt ECO:0000305 location, contradicted by
  membrane localization data); GO:0005515 protein binding (x10 IPI, Bearded-family binding;
  uninformative).
• Developmental processes kept as non-core.

Deep research

• just deep-research-falcon DROME neur --fallback perplexity-lite launched; see status in
  review references (file present only if it completed).

Deep research (falcon) completed

• neur-deep-research-falcon.md generated (second attempt with --timeout 2400). Consistent with
  the review; adds Kalodimou et al. 2023 (Neur also acts as a non-catalytic endocytic
  co-adaptor for Delta; RING-less Neur retains limited activity) and the basic KKIKKR (82-87)
  membrane-targeting region. Not independently verified from primary text here.