insulin and proinsulin

Insulin is a small protein: its gene encodes only 110 amino acids. Actually, this is an immature form known as preproinsulin; the active form is even smaller and consists of two protein chains. To generate the active form, the protein must be processed (Figure 1). The first 24 amino acids form a signal peptide, indicating that the protein should be directed to the secretory apparatus of the cell. These residues are removed once preproinsulin is in the endoplasmic reticulum and the remaining 86 amino acid residues fold into proinsulin (PDB entry 2kqp) (view-1). This is further processed by protease enzymes (known as prohormone convertases) that remove the central section of the molecule leaving two discrete polypeptides of 21 and 30 amino acids in size (Figure 1). The amino-acid sequence of these two peptides was famously determined by Fred Sanger in 1955, for which he was awarded the Nobel Prize in chemistry in 1958. The three dimensional structure of insulin was one of the earliest protein structures to be solved. It was studied by Nobel Prize-winning crystallographer Dorothy Hodgkin. She and her team worked extensively on this from the 1930s, finally determining the structure of porcine insulin (which is only one amino acid different to human) in 1969.