Crystal structures of pyrrolidone-carboxylate peptidase I from Deinococcus radiodurans reveal the mechanism of L-pyroglutamate recognition
Ravindra Makde [1]
Molecular Tour
L-pyroglutamate (pG) is formed by the cyclization of the side chain of glutamate or glutamine amino acid with alpha-amino group at the N-terminus of a polypeptide. This modified residue (pG) cannot be removed by any of the conventional peptidases. Special type of aminopeptidases called pyrrolidone-carboxylate peptidases (PCPs) (EC 3.4.19.-) can remove this unusual amino acid from the peptides or proteins. PCPs are of two types, a) PCPs I, which are cysteine peptidases of C15 family, b) PCPs II are metallopeptidases of M1 family. PCP I is highly conserved enzyme and its homologs have been found from bacteria to human. Many of the physiologically important peptide hormones (TRH, LHRH, GnRH) and antibodies have been shown to possess the pG residue at their N-termini. It seems to have implications in functional regulation of different peptides in both prokaryotes and eukaryotes. However, how these class of enzymes specifically catalyse the removal of pG residue remains mostly unknown. The crystal structures of PCP I from Deinococcus radiodurans (PCPdr) in its pG-free and pG-bound forms at high resolutions has helped to solve this puzzle. Residues responsible for recognizing pG residue are mostly contributed by a flexible loop (loop-A), present near the active site. Phenylalanine residues of loop-A form stacking interactions with the pyrrolidone ring of pG, while Asn18 forms a hydrogen bond with OE of pG. These residues are conserved in all the known PCPs I, including those from mammals. The pG residue of peptides is recognized in the S1 substrate subsite of the enzyme by both van der Waals, and polar interactions, which provide specificity for the pG residue of the peptide.
References
- ↑ Agrawal R, Singh R, Kumar A, Kumar A, Makde RD. Crystal structures of pyrrolidone-carboxylate peptidase I from Deinococcus radiodurans reveal the mechanism of L-pyroglutamate recognition. Acta Crystallogr D Struct Biol. 2019 Mar 1;75(Pt 3):308-316. doi:, 10.1107/S2059798319000676. Epub 2019 Feb 28. PMID:30950401 doi:http://dx.doi.org/10.1107/S2059798319000676
