CCK precursor tail fragment (Cholecystokinin 107-115, desulfated)
A lab-made snippet of the cholecystokinin precursor protein, used as a research tool to study gut satiety signaling, not the active hunger-suppressing hormone itself.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
This is the C-terminal flanking peptide of human pro-cholecystokinin — the nine-residue tail (Ser-Ala-Glu-Glu-Tyr-Glu-Tyr-Pro-Ser) that gets snipped off the cholecystokinin (CCK) precursor when the hormone is matured. It is not the satiety-active CCK-8 hormone itself, but the leftover piece released alongside it. The stored sequence SAEEYEYPS shows the synthetic, desulfated form used as a laboratory reagent; the version that exists inside the body carries sulfate groups on both tyrosines, added in the trans-Golgi before the precursor is cleaved (Eng et al., PNAS 1986). Researchers use this peptide mainly as an antigen for cholecystokinin radioimmunoassays and as a tool substrate for studying how prohormone convertases process pro-CCK.
History
The human pro-CCK precursor was cloned and sequenced by Takahashi and colleagues in 1985, who showed that preprocholecystokinin is a 115-amino-acid protein containing the bioactive CCK sequences and a C-terminal tail (Takahashi et al., PNAS 1985). The porcine equivalent had been cloned a year earlier by Gubler and colleagues, establishing that the same precursor gives rise to all CCK forms in both brain and gut (Gubler et al., PNAS 1984). Soon after, Eng and colleagues raised antibodies against the predicted nonapeptide tail and reported that, in pig brain, the C-terminal flanking peptide (which they termed CAP-9, for "cholecystokinin-associated peptide of 9 residues") carries sulfate on both of its tyrosines — it was undetectable in tissue extracts until the samples were treated with arylsulfatase, which removed the sulfate and exposed the antigen (Eng et al., PNAS 1986). That work established that sulfation of three tyrosines in the pro-CCK C-terminus (one in mature CCK-8 plus two in the flanking peptide) happens before the precursor is cleaved by prohormone convertases. The desulfated synthetic form on this card is the chemistry-friendly version used to generate those antibodies and to study in-vitro processing. Conservation of the CCK precursor architecture across vertebrates was further documented in Xenopus laevis brain by Wechselberger and colleagues (Journal of Molecular Endocrinology, 1995).
What it does
The peptide is released from pro-CCK in equimolar amounts with mature CCK-8: every time an intestinal I-cell or CCK neuron processes the precursor, one molecule of CCK-8 and one molecule of this flanking peptide are produced. No high-affinity receptor or independent physiological function has been demonstrated for the flanking peptide in humans. Its primary uses are technical — as an immunogen for raising antisera that detect CCK-precursor processing, and as a substrate or product peptide to monitor the cleavage activity of prohormone convertase 1 (PC1/PCSK1) and prohormone convertase 2 (PC2/PCSK2) on pro-CCK (Tagen and Beinfeld, Peptides 2005). It is biologically interesting mainly as a marker of pro-CCK maturation rather than as a signaling molecule in its own right.
Mechanism
In the secretory pathway of CCK-producing cells, pro-CCK is first sulfated on three tyrosines by tyrosylprotein sulfotransferase in the trans-Golgi network, then cleaved at paired basic residues (Gly-Arg-Arg motif) by PC1 and PC2 to liberate CCK-8-Gly-Arg-Arg and the C-terminal flanking peptide (Eng et al., PNAS 1986; Tagen and Beinfeld, Peptides 2005). The Gly-Arg-Arg motif on CCK-8 is then trimmed by carboxypeptidase E and the exposed glycine donates its nitrogen to amidate the C-terminal phenylalanine of CCK-8, yielding the mature, biologically active hormone. The flanking peptide produced in this reaction — sulfated on both tyrosines in vivo per Eng and colleagues (PNAS 1986) — shares the trans-Golgi sulfation step with the mature hormone but has no characterized receptor of its own. In vitro, recombinant PC1 and PC2 readily cleave a synthetic substrate spanning the CCK-8/Gly-Arg-Arg/flanking-peptide junction, but cleavage of the full-length pro-CCK at the C-terminal site appears to require additional cellular cofactors that unfold the prohormone (Tagen and Beinfeld, Peptides 2005). The desulfated synthetic form on this card serves as a defined reagent in these biochemical studies. Downstream of the precursor cleavage, mature CCK signals through two G-protein-coupled receptors — CCK-1R (CCKAR, peripheral; sulfation-dependent) and CCK-2R (CCKBR, central and gastric; sulfation-independent) — but those signaling pathways belong to mature CCK, not to this flanking fragment (Liddle, Annual Review of Physiology 1997; Rehfeld, Frontiers in Endocrinology 2017).
Evidence
- Human: No physiological role distinct from CCK-precursor processing has been demonstrated. The flanking peptide has been measured in human and mammalian tissues as an analytical readout of CCK production (Rehfeld, Frontiers in Endocrinology 2017; Miller et al., Frontiers in Endocrinology 2021). Separately, mass-spectrometric measurement of pro-CCK-derived fragments has been advanced as a complementary approach to immunoassay of the labile mature hormone — work demonstrating that precursor-derived peptides can serve as surrogate biomarkers of CCK secretion in human plasma and organoid systems (Foers et al., Journal of Proteome Research 2023).
- Animal: In pig brain, both tyrosines of the C-terminal flanking peptide are fully sulfated and the peptide is recovered in stoichiometry with sulfated CCK-8, consistent with co-secretion from the same processing event (Eng et al., PNAS 1986). Cleavage characteristics in CCK-expressing cells and in vitro have been mapped using recombinant prohormone convertases (Tagen and Beinfeld, Peptides 2005).
- In vitro: Recombinant PC1 and PC2 cleave a synthetic CCK-8-Gly-Arg-Arg-flanking-peptide substrate to liberate CCK-8-Gly-Arg-Arg and the C-terminal nonapeptide; the same cleavage on intact pro-CCK is less efficient and likely requires accessory factors (Tagen and Beinfeld, Peptides 2005). Sulfation of both flanking-peptide tyrosines was confirmed by amino-acid analysis of peptide isolated from brain tissue (Eng et al., PNAS 1986).
Known effects
- Released stoichiometrically with mature CCK-8 from intestinal I-cells and central CCK neurons during pro-CCK processing (Eng et al., PNAS 1986; Tagen and Beinfeld, Peptides 2005).
- In vivo (native) form is doubly sulfated on both tyrosines; the desulfated synthetic peptide on this card is the corresponding standard reagent.
- Serves as a chemical antigen for radioimmunoassays that detect pro-CCK processing products and as a defined substrate or product peptide for in vitro convertase assays.
- No characterized receptor binding, no demonstrated satiety effect, no demonstrated CCK-1R (CCKAR) or CCK-2R (CCKBR) activity — the biological signaling of CCK is carried by the upstream CCK-8 portion of the precursor, not by this flanking fragment (Liddle, Annual Review of Physiology 1997; Rehfeld, Frontiers in Endocrinology 2017).
Regulatory status
Not a drug. The peptide has no approved therapeutic indication in any jurisdiction and no clinical-development program. It is used as a research reagent — peptide antigen, radioimmunoassay standard, or convertase substrate. The only CCK-derived compound with regulatory approval is sincalide (synthetic sulfated CCK-8, brand name Kinevac), used as a diagnostic agent for gallbladder scintigraphy and pancreatic function testing; this is a separate molecule, corresponding to the bioactive CCK-8 region of the precursor rather than the C-terminal flanking peptide that this card represents.
Related peptides
- Mature CCK-8 hormone — the biologically active fragment cleaved from the same pro-CCK precursor (UniProt P06307, residues 96–103). The flanking peptide on this card and CCK-8 are released together when PC1/PC2 process pro-CCK (Tagen and Beinfeld, Peptides 2005).
- CCK-58, CCK-33, CCK-22 — longer, intermediately-processed forms of CCK that contain the CCK-8 sequence but retain different lengths of upstream pro-region (Reeve et al., Annals of the New York Academy of Sciences 1994; Rehfeld, Frontiers in Endocrinology 2017).
- CCK-4 — the C-terminal tetrapeptide (Trp-Met-Asp-Phe-NH₂) of CCK-8; used in psychopharmacology research as a CCK-2R panic-induction probe (Bradwejn et al., Archives of General Psychiatry 1991). Distinct from this card's peptide, which is downstream of CCK-8 on the precursor rather than within it.
- Radiolabeled CCK/gastrin analogs — clinical-research CCK-2R-targeted peptides for tumor imaging and therapy (Roosenburg et al., Amino Acids 2011); a separate, receptor-binding application within the broader CCK/gastrin peptide family.
Open questions
- Whether the C-terminal flanking peptide has any receptor-mediated or paracrine function distinct from being a processing byproduct remains unresolved — no high-affinity binding site has been identified.
- Whether circulating concentrations of the flanking peptide could serve as a clinically useful biomarker of CCK secretion — complementing or substituting for mature CCK-8 immunoassays — has not been systematically evaluated in humans, though the broader concept of using pro-CCK-derived fragments as secretion surrogates has been validated for other parts of the precursor (Foers et al., Journal of Proteome Research 2023).
- The cellular cofactors required to expose the C-terminal cleavage site of intact pro-CCK to PC1 and PC2 in vivo are not fully characterized (Tagen and Beinfeld, Peptides 2005).
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
Could this peptide be used to measure two enzymes at the same time, one that cuts proteins and one that adds sulfate tags?
If this works, researchers would gain a simpler, single-peptide tool for studying secretory processing, potentially speeding up drug discovery for conditions linked to faulty hormone maturation or for finding inhibitors of sulfation enzymes involved in inflammation and HIV entry.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.8764180541038513 | boltz-2 |
| ranking score | 0.7855430245399475 | boltz-2 |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 1.202 | global PDE — lower = better |
| disorder | NaN | fraction disordered |
▸3-letter notation
▸recipeboltz-2 1.0
| parameter | value |
|---|---|
| model | boltz-2 1.0 |
| weights | — |
| hardware | nvidia_nim_api |
| mlx version | — |
| python | — |
| random seed | — |
| msa strategy | none |
| diffusion samples | 1 |
| runtime | — |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
▸citationbibtex
@peptide{pep10640,
sequence = {SAEEYEYPS},
target = {cckar},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}