Question

Explain how human pro-insulin is processed in the cell to become a fully mature functional insulin.

Hint:

Remember the order: Pro-insulin (A-B-C) $\rightarrow$ Disulfide bonds form $\rightarrow$ C peptide is cut out $\rightarrow$ Mature insulin (A and B linked). The C peptide is a "connecting" piece that is removed.

Answer 1

Human pro-insulin is a precursor molecule that undergoes post-translational modification to become mature insulin. It consists of three polypeptide chains: A, B, and C. During maturation, the C peptide is cleaved and removed, leaving the A and B chains linked by disulfide bonds, forming the functional insulin molecule. Solution: Human insulin is synthesized in the pancreatic β-cells as a precursor molecule called pro-insulin. Pro-insulin is a single polypeptide chain that contains three distinct regions: • Bchain: A short polypeptide chain at the N-terminus. • Cpeptide: A connecting peptide chain in the middle. • Achain: Another short polypeptide chain at the C-terminus.The conversion of pro-insulin to mature, functional insulin involves a specific post-translational processing event: 1. Formation of Disulfide Bonds: Within the endoplasmic reticulum (ER), pro-insulin undergoes folding, and disulfide bonds are formed between specific cysteine residues in the A and B chains. These disulfide bonds are crucial for the correct three-dimensional structure and stability of the insulin molecule. Typically, there are two disulfide bonds linking the A and B chains and one intra-chain disulfide bond within the A chain. 2. Cleavage by Endopeptidases: Pro-insulin is then transported from the ER to the Golgi apparatus, where it undergoes proteolytic cleavage. Specific endopeptidases, called prohormone convertases (PC1/3 and PC2), cleave the pro-insulin molecule at two specific sites. These cleavage events excise the C peptide, which is located between the Band Achains. 3. Release of Mature Insulin: The removal of the C peptide results in the formation of the mature insulin molecule, which consists of the A chain and the B chain linked together by the disulfide bonds. The C peptide is stored and secreted along with insulin but has no direct role in glucose metabolism. 4. Packaging and Secretion: Mature insulin molecules, along with the cleaved C peptide, are packaged into secretory granules within the β-cells. Upon stimulation by high blood glucose levels, these granules fuse with the plasma membrane, releasing insulin and the Cpeptide into the bloodstream. The precise and regulated processing of pro-insulin is essential for producing the biologically active form of insulin that can effectively regulate blood glucose levels. The removal of the C peptide is critical for the proper interaction of the A and B chains with the insulin receptor.