RORB notes

Provenance note: Provider deep research for RORB failed (Falcon returned HTTP 402
Payment Required; Perplexity is not configured). No RORB-deep-research-*.md file exists.
This manual synthesis replaces it. It is built from the UniProt record (Q92753), the cached
publications in publications/, and PubMed E-utilities searches used to locate key primary
papers, which were then cached with just fetch-pmid.

Identity and structure

• RORB (RAR-related orphan receptor B; NR1F2; historic name RZR-beta) is a nuclear
  receptor of the NR1 subfamily, with a C4-type zinc-finger DNA-binding domain (Pfam
  PF00105; InterPro IPR001628, IPR044101 NR_DBD_ROR) and a ligand-binding domain (PF00104).
  PANTHER PTHR45805:SF6 "NUCLEAR RECEPTOR ROR-BETA".
• Two isoforms come from alternative promoters: isoform 1 (RORbeta1, Q92753-1) and
  isoform 2 (RORbeta2, Q92753-2, the displayed sequence). They differ only at the N-terminus.
  [file:human/RORB/RORB-uniprot.txt "Event=Alternative promoter usage; Named isoforms=2;"]

Molecular function: monomeric DNA-binding transcription factor

• Binds RORE half-sites as a monomer: PMID:7935491 and an
  A/T 5' extension improves binding PMID:7935491.
• Constitutive transactivation: PMID:7935491.
• LBD structure: PMID:11689423; PMID:11689423
• Retinoids as inverse agonists: PMID:12958591; PMID:12958591
• Human RORB was included in a genome-scale HT-SELEX study of TF DNA-binding specificity
  (PMID:28473536); RORB is not named in the main text, so the IDA is accepted on the
  curator's reading of the supplementary data.
• Target gene: Opn1sw (S opsin), with CRX synergy PMID:16574740; PMID:16574740.
• Nuclear localization: PMID:27352968.

Melatonin

The RZR/ROR family was once proposed to bind melatonin. That proposal was later withdrawn
and is not part of the current view. In RORbeta-knockout mice, pineal melatonin rhythms and
melatonin-induced phase shifts are normal: PMID:17303680. RORB has no seven-transmembrane
domain, so GO:0008502 melatonin receptor activity (a GPCR-type receptor activity in practice)
and the GPCR signaling inference built on it are not supported.

Biological roles (mostly mouse genetics)

• Retina, rods: PMID:19805139;
  PMID:19805139
• Retina, cones: PMID:16574740
• Retina, interneurons (isoform RORbeta1): PMID:23652001; PMID:23652001.
• Knockout phenotype overall: PMID:9670004
• Circadian period: PMID:9670004; confirmed in another
  background PMID:17303680. This is a downstream phenotype. It is unclear whether RORB acts
  in the core clock or through retinal/SCN development.
• Neocortex layer IV / barrels: PMID:21799210; PMID:21799210.
• Bone: PMID:22189870; overexpression in MC3T3-E1 cells PMID:22189870. This is a cell-line overexpression result; I treat it as non-core.
• Human disease: heterozygous loss-of-function variants and deletions cause generalized
  epilepsy, often with absences, sometimes with intellectual disability PMID:27352968.

Interaction annotation

The GO:0005515 IPI (PMID:23555304) comes from a circadian yeast two-hybrid screen
PMID:23555304. The partner is mouse CLOCK (O08785), and RORB was a strong auto-activator as bait
PMID:23555304.
No functional consequence is shown, so the protein binding term is removed as uninformative.
The interaction itself is not disputed.

Alzheimer disease context (selective vulnerability)

Leng et al. 2021 (PMID:33432193) used snRNA-seq of caudal entorhinal cortex and identified
RORB as a marker of excitatory neurons that are depleted early in AD
PMID:33432193. The link to RORB's own function is explicitly a hypothesis:
PMID:33432193

Assessment: In the material reviewed here, nothing ties RORB activity (DNA binding,
target-gene regulation, retinoid modulation) causally to tau vulnerability. There is no
RORB knockdown/overexpression in a tauopathy model, no RORB target-gene set tested for
vulnerability, and no human genetic association of RORB with AD in the sources read. RORB
currently labels the vulnerable population (layer II/III-like entorhinal excitatory neurons).
It does not explain why those neurons are vulnerable. GO annotation for RORB should therefore
carry nothing AD-related. This is recorded as a suggested question/experiment in the review.

Curation summary

• Core MF: nuclear receptor activity (GO:0004879), with sequence-specific RORE binding.
• Core BP: positive regulation of transcription by RNA pol II; retinal rod and cone
  development; amacrine cell differentiation (isoform 1).
• Removed: melatonin receptor activity (IBA), GPCR signaling pathway (IEA inferred from it),
  protein binding (IPI).