Potato carboxypeptidase inhibitor explained

Potato carboxypeptidase inhibitor (PCI) is a naturally occurring protease inhibitor peptide in potatoes that can form complexes with several metallo-carboxypeptidases, inhibiting them in a strong competitive way with a Ki in the nanomolar range.
PCI consists of 39 amino acids (MW 4295 Da) forming a 27-residue globular core stabilized by three disulfide bridges and a C-terminal tail with residues 35–39. PCI contains a small cysteine-rich module, called a T-knot scaffold, that is shared by several different protein families, including the EGF family.

Medicinal properties

Because of the structural similarities with EGF, PCI inhibits tumor cell growth. Mechanism of action is inhibition of receptor dimerization and receptor trans-autophosphorylation induced by epidermal growth factor (EGF). PCI blocks the formation and activation of ErbB1/ErbB-2 (EGFR and HER2) heterodimers that have a prominent role in carcinoma development.
PCI also inhibits transforming growth factor alpha (TGF-alpha).In addition for pancreatic enzymes carboxypeptidase A and B, PCI also inhibits carboxypeptidase R without affecting the activity of carboxypeptidase N in the circulation and have therefore use in thrombolytic therapy (blood clot lysis).

References

1. Book: Hass JM, Ryan CA . Carboxypeptidase inhibitor from potatoes . Proteolytic Enzymes, Part C . 80 . Proteolytic Enzymes, Part C . 778–91 . 1981 . 10.1016/S0076-6879(81)80060-2 . Methods in Enzymology . 978-0-12-181980-4 .
2. McDonald NQ, Hendrickson WA . A structural superfamily of growth factors containing a cystine knot motif . Cell . 73 . 3 . 421–4 . May 1993 . 8490958 . 10.1016/0092-8674(93)90127-C. 43834128 . free .
3. Sun PD, Davies DR . The cystine-knot growth-factor superfamily . Annu Rev Biophys Biomol Struct . 24 . 269–91 . 1995 . 7663117 . 10.1146/annurev.bb.24.060195.001413 .
4. Lin SL, Nussinov R . A disulphide-reinforced structural scaffold shared by small proteins with diverse functions . Nat. Struct. Biol. . 2 . 10 . 835–7 . October 1995 . 7552703 . 10.1038/nsb1095-835 . 26918151 .
5. Blanco-Aparicio C, Molina MA, Fernández-Salas E . etal . Potato carboxypeptidase inhibitor, a T-knot protein, is an epidermal growth factor antagonist that inhibits tumor cell growth . J. Biol. Chem. . 273 . 20 . 12370–7 . May 1998 . 9575190 . 10.1074/jbc.273.20.12370. free .
6. Sitjà-Arnau M, Molina MA, Blanco-Aparicio C . etal . Mechanism of action of potato carboxypeptidase inhibitor (PCI) as an EGF blocker . Cancer Lett. . 226 . 2 . 169–84 . August 2005 . 16039955 . 10.1016/j.canlet.2005.01.025 .
7. Nagashima M, Werner M, Wang M . etal . An inhibitor of activated thrombin-activatable fibrinolysis inhibitor potentiates tissue-type plasminogen activator-induced thrombolysis in a rabbit jugular vein thrombolysis model . Thromb. Res. . 98 . 4 . 333–42 . May 2000 . 10822080 . 10.1016/S0049-3848(00)00184-5.
8. Redlitz A, Tan AK, Eaton DL, Plow EF . Plasma carboxypeptidases as regulators of the plasminogen system . J. Clin. Invest. . 96 . 5 . 2534–8 . November 1995 . 7593646 . 185916 . 10.1172/JCI118315.

Further reading

• Ryan CA, Hass GM, Kuhn RW . Purification and properties of a carboxypeptidase inhibitor from potatoes . J. Biol. Chem. . 249 . 17 . 5495–9 . 10 September 1974. 10.1016/S0021-9258(20)79755-3 . 4415398 . free .
• Chang JY, Canals F, Schindler P, Querol E, Avilés FX . The disulfide folding pathway of potato carboxypeptidase inhibitor . J. Biol. Chem. . 269 . 35 . 22087–94 . 2 September 1994. 10.1016/S0021-9258(17)31759-3 . 8071332 . free .
• Smith JA, Francis SH, Corbin JD . Autophosphorylation: a salient feature of protein kinases . Mol. Cell. Biochem. . 127–128 . 51–70 . November 1993 . 7935362 . 10.1007/BF01076757 . 36865501 .

See also

Scaffold (disambiguation)
Protein kinase
Chemotherapy
Thrombolysis
Cancer research