Functional Considerations: Insulin Synthesis, An Example of Posttranslational Processing
Insulin is a small protein consisting of two polypeptide chains joined by disulfide bridges. Its biosynthesis presents a clear example of the importance of posttranslational processing in the achievement of the final, active structure of a protein.
Insulin is originally synthesized as a single 110-amino acid polypeptide chain with a molecular weight of about 12,000 Da. This polypeptide is called preproinsulin. Preproinsulin is reduced to a polypeptide with a molecular weight of about 9000 Da, called proinsulin, as the molecule is inserted into the cis-ternae of the rER. Proinsulin is a single polypeptide chain of 81 to 86 amino acids that has the approximate shape of the letter G. Two disulfide bonds connect the bar of the G to the top loop.
During packaging and storage of proinsulin in the Golgi apparatus, a cathepsin-like enzyme cleaves most of the side of the loop, leaving the bar of the G as an A chain of 21 amino acids cross-linked by the disulfide bridges to the top of the loop, which becomes the B chain of 30 amino acids. The 35-amino acid peptide removed from the loop is called a Cpeptide (connecting peptide). It is stored in the secretory vesicles and released with the insulin in equimolar amounts. No function has been identified for the C peptide. However, measurement of circulating levels of C peptide sometimes provides important clinical information on the secretory activity of B cells.
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