PROLINE MOTIFS IN PEPTIDES AND THEIR BIOLOGICAL PROCESSING

Many biologically important peptide sequences contain proline. It conf ers unique conformational constraints on the peptide chain in that the side-chain is cyclized back onto the backbone amide position. Inside an alpha-helix the possibility of making hydrogen bonds to the precedi ng turn is lost and a kink will be introduced. The conformational rest rictions imposed by proline motifs in a peptide chain appear to imply important structural or biological functions as can be deduced from th eir often remarkably high degree of conservation as found in many prot eins and peptides, especially cytokines, growth factors, G-protein-cou pled receptors, V3 loops of the HIV envelope glycoprotein gp120, and n euro- and vasoactive peptides. Only a limited number of peptidases are known to be able to hydrolyze proline adjacent bonds. Their activity is influenced by the isomeric state (cis-trans) as well as the positio n of proline in the peptide chain. The three proline specific metallo- peptidases (aminopeptidase P, carboxypeptidase P and prolidase) are ac tivated by Mn2+, whereas the three serine type peptidases cleaving a p ost proline bond (prolyl oligopeptidase, dipeptidyl peptidase IV, and prolylcarboxypeptidase) share the sequential order of the catalytic Se r-Asp-His triade, which differentiates them from the chymotrypsin (His -Asp-Ser) and subtilisin (Asp-His-Ser) families. An endo or C terminal Pro-Pro bond and an endo pre-Pro peptide bond possess a high degree o f resistance to any mammalian proteolytic enzyme.