Proline motifs in peptides and their biological processing

Abstract

Many biologically important peptide sequences contain proline. It confers 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 preceding turn is lost and a kink will be introduced. The conformational restrictions imposed by proline motifs in a peptide chain appear to imply important structural or biological functions as can be deduced from their often remarkably high degree of conservation as found in many proteins and peptides, especially cytokines, growth factors, G-protein-coupled receptors, V3 loops of the HIV envelope glycoprotein gp 120, and neuro- 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 position of proline in the peptide chain. The three proline specific metallo-peptidases (aminopeptidase P, carboxypeptidase P and prolidase) are activated by Mn2+, whereas the three serine type peptidases cleaving a post proline bond (prolyl oligopeptidase, dipeptidyl peptidase IV, and prolylcarboxypeptidase) share the sequential order of the catalytic Ser-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 of resistance to any mammalian proteolytic enzyme.

Truncation of Macrophage-derived Chemokine by CD26/ Dipeptidyl-Peptidase IV beyond Its Predicted Cleavage Site Affects Chemotactic Activity and CC Chemokine Receptor 4 Interaction

“…stromal cell-derived factor-1␣ (SDF-1␣) and RANTES). This Pro residue protects these molecules from degradation by most aminopeptidases (4). Some short peptides, including substance P and gastrin-releasing peptide have been known for some time as effective substrates for CD26/DPP IV (3).…”

“…Surprisingly, CD26/DPP IV not only removed the expected Gly 1 -Pro 2 dipeptide from the NH 2 terminus of macrophage-derived chemokine (MDC) but subsequently also the Tyr 3 -Gly 4 …”

The amino terminus extension in the long dipeptidyl peptidase 9 isoform contains a nuclear localization signal targeting the active peptidase to the nucleus

“…While many peptidases are redundant in their activity and selectivity, only a few can cleave a peptide bond following a proline residue because of its rigid ring structure (URL: http://merops.sanger.ac.uk; [1,2]). Members of the S9B/DPPIV family are serine amino peptidases with the unique ability to cleave off N-terminal dipeptides from proteins/peptides having a proline residue at position 2 (X aa P).…”

Influence of flanking sequences on presentation efficiency of a CD8+ cytotoxic T-cell epitope delivered by parvovirus-like particles

“…The flexibility of the epitope and the capacity of the system to adopt multiple conformations, which could facilitate cleavage by host proteases, seem to be important, since the insertion of a proline between the two OVA epitopes prevents its correct antigen presentation. However, the negative result observed with Pro was not totally unexpected, since Pro is well known as a hindrance to many proteases (Vanhoof et al, 1995;Yaron & Naider, 1993) and has also been shown to interfere with TAP (transporter associated with antigen presentation)-dependent transport of antigenic peptides when occupying certain positions within the peptide (Neisig et al, 1995).…”