AGR3 notes

2026-06-03 PN Proteostasis review

• Generated inputs with just fetch-gene human AGR3; this created the UniProt record, GOA table, and a 10-entry review stub from 38 GOA rows. Falcon deep research completed at genes/human/AGR3/AGR3-deep-research-falcon.md.
• PN projection reviewed: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv:219 proposes GO:0003756 protein disulfide isomerase activity for AGR3 from ER proteostasis|Folding enzyme|Protein disulfide isomerases.
• Conservative decision: do not add GO:0003756 for AGR3. AGR3 is ER-retained and thioredoxin-like, but Falcon synthesis highlights that AGR3 lacks the canonical PDI CXXC/WCXXC motif and "is not a canonical disulfide isomerase" [file:human/AGR3/AGR3-deep-research-falcon.md "Although structurally in the PDI/thioredoxin family, AGR3's DCYQS motif (lacking the second cysteine) supports the view that AGR3 is not a canonical disulfide isomerase"]. This makes the PN projection a family/context projection rather than a safe gene-level GO addition.
• Strongest supported physiological function: ER-localized AGR3 is required for calcium-mediated regulation of airway ciliary beat frequency and mucociliary clearance PMID:25751668.
• ER localization is supported by the KDEL-receptor/retention motif study PMID:18086916 and by the airway paper's ciliated-cell ER-resident framing PMID:25751668.
• Dystroglycan binding is retained as non-core. The underlying evidence is yeast two-hybrid interaction with alpha-dystroglycan/DAG1 and C4.4a/LYPD3 in a cancer context PMID:12592373, with the authors noting that clinical-context confirmation was still needed PMID:12592373.
• Generic protein binding rows from high-throughput interactome maps were removed, except the PMID:12592373 row was modified to the more specific existing dystroglycan binding term.

2026-10-05 OpenScientist follow-up

• Critically evaluated genes/human/AGR3/AGR3-hypotheses/kgap-agr3-noncanonical-pdi-redox-clients/openscientist.md. The report is a literature synthesis rather than a new bioinformatics analysis, and it reinforced the Falcon-based decision not to add GO:0003756 protein disulfide isomerase activity for AGR3 [file:human/AGR3/AGR3-hypotheses/kgap-agr3-noncanonical-pdi-redox-clients/openscientist.md "- Do not assign a specific catalytic molecular function (e.g., GO:0003756\n protein-disulfide isomerase activity, or generic oxidoreductase) to AGR3 by IDA/IMP"].
• Treated the report's PMIDs as authoritative but its DOI strings as unchecked because one AGR3 crystal-structure DOI was approximate in the report; PMID:29969106 is the 2018 human AGR3 crystal-structure paper and supports a noncanonical single-cysteine active-site motif.
• Narrowed the proposed AGR3 airway process from GO:0003351 epithelial cilium movement involved in extracellular fluid movement plus GO:0019722 calcium-mediated signaling to GO:0003356 regulation of cilium beat frequency. QuickGO places GO:0060296 regulation of cilium beat frequency involved in ciliary motility under GO:0060294 cilium movement involved in cell motility, so the broader frequency term is the better fit for airway epithelial cilia that move extracellular fluid. The mouse Agr3 knockout paper supports reduced airway CBF and impaired mucociliary clearance PMID:25751668, while calcium-free perfusion shows the phenotype depends on calcium-regulated beating and does not by itself show that AGR3 performs a calcium-signaling step.

2026-11-04 ORGANELLES ER batch 1 (endoplasmic reticulum rows)

• Rows: three GO:0005783 rows (IBA GO_REF:0000033, is_active_in; IEA GO_REF:0000120 ARBA + SL-0095; IDA GO_REF:0000052 HPA), all ACCEPT. No ER sub-compartment row existed.
• IBA check: interpro/panther/PTHR15337/PTHR15337-paint.tsv has the GO:0005783 IBD at PTN001034224 seeded by MGI:1344405, MGI:1913323, RGD:1305960, O95881 (TXNDC12), O95994 (AGR2) and Q8TD06 (AGR3 itself, expected). The only NOT (IRD, PTN009024331) is on a Xenopus branch (taxon:8355).
• is_active_in: no AGR3 molecular activity has been shown in the ER (PDI-like activity unproven), so the qualifier is not substantiated by activity evidence; the location is right, qualifier left unchanged, verdict recorded in the row reason.
• IEA check: the UniProt "Endoplasmic reticulum" line is curated from experiments (ECO:0000269, PubMed:18086916, PubMed:25751668).
• NEW GO:0005788 endoplasmic reticulum lumen (IC, PMID:18086916): (1) UniProt "FT SIGNAL 1..21" with ECO:0000269|PubMed:15340161 and no TM segment, so soluble; (2) "FT MOTIF 163..166 /note=\"Prevents secretion from ER\"" (ECO:0000269|PubMed:18086916), and in PMID:18086916 PMID:18086916; (3) PDI-family relatives AGR2/ERp18 under the same PAINT node are lumenal (supportive only). IC because the motif assay is on an overexpressed tagged construct and no protease-protection assay exists. core_functions left at the root.