Insulin processing

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Generation of insulin containing secretory granules from newly synthesized proinsulin in the lumen of the endoplasmic reticulum (ER) involves formation of proinsulin intramolecular disulfide bonds, formation of proinsulin zinc calcium complexes, proteolytic cleavage of proinsulin to yield insulin and C peptide, and translocation of the granules across the cytosol to the plasma membrane (Dodson & Steiner 1998).
Transcription of the human insulin gene INS is annotated as part of the pathway “Regulation of gene expression in beta cells” (see reaction R-HSA-211289). The preproinsulin mRNA is translated by ribosomes at the rough endoplasmic reticulum (ER) and the preproinsulin enters the secretion pathway by virtue of its signal peptide, which is co-translationally cleaved to yield proinsulin.
In the process annotated here, within the ER, three intramolecular disulfide bonds form in proinsulin, mediated by P4HD (PDI1A) and ERO1B proteins. Correctly folded, disulfide-bonded proinsulin then moves via vesicles from the ER to the Golgi Complex where it forms complexes with zinc and calcium.
Proinsulin zinc calcium complexes bud in vesicles from the trans Golgi to form immature secretory vesicles (secretory granules) in the cytosol. Within the immature granules, endoproteases PCKS1 and PCKS2 (Prohormone Convertases 1 and 2) cleave proinsulin at two sites and CPE (Carboxypeptidase E) removes additional amino acid residues to yield the cystine bonded A and B chains of mature insulin and the C peptide, which will be secreted with the insulin. The insulin zinc calcium complexes form insoluble crystals within the granule.
The insulin containing secretory granules are then translocated across the cytosol to the inner surface of the plasma membrane. Translocation occurs initially by attachment of the granules to Kinesin 1, which motors along microtubules, and then by attachment to Myosin Va, which motors along the microfilaments of the cortical actin network.
A pancreatic beta cell contains about 10,000 insulin granules of which about 1,000 are docked at the plasma membrane and 50 are readily releasable in immediate response to stimulation by glucose or other secretogogues. Docking is due to interaction between the Exocyst proteins EXOC3 on the granule membrane and EXOC4 on the plasma membrane. Exocytosis is accomplished by interaction between SNARE type proteins Syntaxin 1A and Syntaxin 4 on the plasma membrane and Synaptobrevin 2/VAMP2 on the granule membrane. Exocytosis is a calcium dependent process due to interaction of the calcium binding membrane protein Synaptotagmin V/IX with the SNARE type proteins.
Literature References
PubMed ID Title Journal Year
16714477 Insulin vesicle release: walk, kiss, pause ... then run

Rutter, GA, Hill, EV

Physiology (Bethesda) 2006
11815463 Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion

Straub, SG, Yajima, H, Gunawardana, S, Sharp, GW, Daniel, S, Bratanova-Tochkova, TK, Mulvaney-Musa, J, Cheng, H, Schermerhorn, T, Liu, YJ

Diabetes 2002
11815450 Molecular determinants of regulated exocytosis

Gerber, SH, Südhof, TC

Diabetes 2002
16549443 Regulation of the insulin gene by glucose and fatty acids

Poitout, V, Stein, R, Robertson, RP, Harmon, JS, Artner, I, Hagman, D

J Nutr 2006
9631292 The role of assembly in insulin's biosynthesis

Steiner, D, Dodson, G

Curr Opin Struct Biol 1998
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