Insulin possesses two polypeptide chains denoted A and B that are linked by disulfide bonds. Upon denaturation by reduction of the SH groups of insulin, followed by reoxidation, only 7% of the hormone activity is recovered. This is the level of activity expected for random pairing of cysteine residues to form disulfide bonds. How can these data be reconciled with the hypothesis that the amino acid sequence directs protein folding?
Answer
Insulin is synthesized as preproinsulin that is proteolytically processed in the β cells of the islets of Langerhans in the pancreas, to give proinsulin. After synthesis and folding, a section of the molecule (the C peptide) is excised, leaving the A and B peptides connected via disulfide bonds. Thus, native insulin, lacking the C peptide, lacks some of the information necessary to direct the folding process.
