PCSK1 cleaves proinsulin to yield Insulin(25-56) and Insulin(57-110)

Stable Identifier
Reaction [transition]
Homo sapiens
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PCSK1 cleaves C-terminal to arginine-56 in proinsulin to yield the B chain (plus two C-terminal arginine residues) and a peptide containing the C-peptide and the A chain ( Jackson et al. 2003, Jackson et al. 1997 and inferred from rat Pcsk1). The reaction occurs in immature secretory granules (Orci et al. 1985).
Overall, proinsulin in proinsulin-zinc-calcium complexes is cleaved by endopeptidases PCSK1 (Prohormone Convertase 1/3) and PCSK2 (Prohormone Convertase 2). The exopeptidase CPE (Carboxypeptidase E, also called Carboxypeptidase H) removes 2 amino acids from the carboxyl termini of the resulting B chain (INS 25-56) and C-peptide (INS 57-87). In the major pathway of processing PCSK1 cleaves between the B chain and the C-peptide, CPE removes two arginine residues from the C-terminus of the B chain, PCSK2 cleaves between the C-peptide and the A chain (INS 90-110), and CPE removes an arginine residue and a lysine residue from the C-terminus of the C-peptide. Unlike the proinsulin-zinc calcium complex, the insulin-zinc-calcium complex is not soluble and forms crystals inside the secretory granules.

Literature References
PubMed ID Title Journal Year
14617756 Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency

Nicole, TM, Lindley, KJ, Varro, A, Becker, KL, Polonsky, KS, Dockray, GJ, Jackson, RS, Farooqi, IS, Hutton, JC, Brubaker, PL, Middleton, SJ, Holst, JJ, Creemers, JW, Corvol, P, Raffin-Sanson, ML, Bertagna, X, Ostrega, D, Dattani, MT, O'Rahilly, S, Milla, PJ, White, A, Hussain, K

J Clin Invest 2003
3896518 Direct identification of prohormone conversion site in insulin-secreting cells

Vassalli, JD, Madsen, O, Amherdt, M, Perrelet, A, Orci, L, Ravazzola, M

Cell 1985
9207799 Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene

Creemers, JW, Sanders, L, Raffin-Sanson, ML, Jackson, RS, Montague, CT, O'Rahilly, S, Hutton, JC, Ohagi, S

Nat Genet 1997
Catalyst Activity

serine-type endopeptidase activity of PC1:calcium cofactor [secretory granule lumen]

Inferred From
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