POMC - Pro-opiomelanocortin Notes

Polyprotein Biology

POMC is a paradigm for post-translational processing - fundamentally different from alternative splicing. A single mRNA produces ONE precursor protein that is then proteolytically cleaved into multiple bioactive peptides with distinct and sometimes antagonistic functions.

Cleavage Products (from UniProt)

Peptide Residues PRO ID Function
Signal peptide 1-26 - Secretion
NPP 27-102 PRO_0000024966 Unknown
Gamma-MSH 77-87 PRO_0000024967 Pigmentation
Potential peptide 105-134 PRO_0000024968 Unknown
ACTH 138-176 PRO_0000024969 Stimulates cortisol release
Alpha-MSH 138-150 PRO_0000024970 Anorexigenic, pigmentation
CLIP 156-176 PRO_0000024971 Unknown
Beta-LPH 179-267 PRO_0000024972 Lipotropic
Gamma-LPH 179-234 PRO_0000024973 Lipotropic
Beta-MSH 217-234 PRO_0000024974 Pigmentation
Beta-endorphin 237-267 PRO_0000024975 Orexigenic opiate
Met-enkephalin 237-241 PRO_0000024976 Opiate

Tissue-Specific Processing

The key insight is that different tissues produce different peptide combinations:

  1. Anterior pituitary (corticotrophs): ACTH is the primary product
  2. ACTH stimulates adrenal cortex to release cortisol

  3. Processing stops at ACTH level - alpha-MSH is NOT produced here

  4. Intermediate pituitary (minimal in adult humans): MSH peptides

  5. ACTH is further cleaved to produce alpha-MSH and CLIP

  6. This is the main source of MSH in other species

  7. Hypothalamus (arcuate nucleus): Both alpha-MSH and beta-endorphin

  8. Alpha-MSH: reduces appetite (anorexigenic) via MC4R
  9. Beta-endorphin: stimulates appetite (orexigenic), pain modulation

Antagonistic Functions Within Same Precursor

This is critical for GO annotation:
- Alpha-MSH: Anorexigenic (suppresses appetite)
- Beta-endorphin: Orexigenic (stimulates appetite)

Both peptides are produced in the same hypothalamic neurons! The balance between them affects feeding behavior.

GO Annotation Challenges

  1. Gene-level vs peptide-level: GO annotates the gene, but functions are peptide-specific
  2. Antagonistic functions: The gene should NOT be simply annotated to both "positive regulation of appetite" and "negative regulation of appetite" without context
  3. Tissue specificity: ACTH function is relevant for pituitary; MSH function for hypothalamus
  4. PRO ontology: UniProt provides PRO IDs for each peptide - ideal for peptide-specific GO annotation

Key References

Comparison to Alternative Splicing

Feature Alternative Splicing (e.g., BCL2L1) Polyprotein Processing (POMC)
Mechanism Pre-mRNA splicing Post-translational proteolysis
Regulation point Nucleus (splicing) ER/Golgi/secretory pathway
mRNA products Multiple distinct mRNAs Single mRNA
Protein products Different full-length proteins Multiple peptides from one precursor
Tissue specificity Splice factor expression Prohormone convertase expression
Example enzymes - PC1/3, PC2, carboxypeptidases

Questions for GO Curation

  1. Should annotations be made at the PRO level for peptide-specific functions?
  2. How to handle antagonistic functions from the same gene?
  3. Is "regulation of appetite" appropriate when the gene produces both appetite-increasing and appetite-decreasing peptides?

Falcon deep research integration - 2026-05-12

Falcon deep research was added as POMC-deep-research-falcon.md. It reinforces
the existing review's main caution: POMC should be treated as a secreted
prohormone precursor whose cleavage products carry distinct receptor-binding and
physiological activities [file:human/POMC/POMC-deep-research-falcon.md
"Pro-opiomelanocortin (POMC) is best curated in GO as a secreted
prohormone precursor that is sorted to regulated secretory granules and
proteolytically processed in a tissue-specific manner to yield multiple
bioactive peptides (ACTH, α/β/γ-MSH, β-endorphin; enkephalin motifs embedded in
the β-LPH/β-endorphin region)."].

The report specifically supports keeping the generic protein-binding annotation
removed and preferring peptide/receptor-specific terms over broad GPCR or
behavior terms [file:human/POMC/POMC-deep-research-falcon.md "Generic protein
binding / identical protein binding: Do not annotate generic binding
(including “identical protein binding”) unless there is direct biochemical
interaction evidence for the relevant molecular entity (precursor vs peptide)."]
and [file:human/POMC/POMC-deep-research-falcon.md "Melanocortin receptor
binding vs generic GPCR binding: Prefer melanocortin receptor binding
terms, with MC2R specificity for ACTH explicitly supported; do not use
generic “GPCR binding” for POMC gene product as a catch-all."].