The structure of Leishmania mexicana ICP provides evidence for convergent evolution of cysteine peptidase inhibitors

Smith, B.O. , Picken, N.C., Westrop, G.D., Bromek, K., Mottram, J.C. and Coombs, G.H. (2006) The structure of Leishmania mexicana ICP provides evidence for convergent evolution of cysteine peptidase inhibitors. Journal of Biological Chemistry, 281, pp. 5821-5828. (doi:10.1074/jbc.M510868200)

Full text not currently available from Enlighten.

Abstract

Clan CA, family C1 cysteine peptidases (CPs) are important virulence factors and drug targets in parasites that cause neglected diseases. Natural CP inhibitors of the I42 family, known as ICP, occur in some protozoa and bacterial pathogens but are absent from metazoa. They are active against both parasite and mammalian CPs, despite having no sequence similarity with other classes of CP inhibitor. Recent data suggest that Leishmania mexicana ICP plays an important role in host-parasite interactions. We have now solved the structure of ICP from L. mexicana by NMR and shown that it adopts a type of immunoglobulin-like fold not previously reported in lower eukaryotes or bacteria. The structure places three loops containing highly conserved residues at one end of the molecule, one loop being highly mobile. Interaction studies with CPs confirm the importance of these loops for the interaction between ICP and CPs and suggest the mechanism of inhibition. Structure-guided mutagenesis of ICP has revealed that residues in the mobile loop are critical for CP inhibition. Data-driven docking models support the importance of the loops in the ICP-CP interaction. This study provides structural evidence for the convergent evolution from an immunoglobulin fold of CP inhibitors with a cystatin-like mechanism.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Westrop, Mr Gareth and Picken, Dr Nichola and Smith, Dr Brian and Coombs, Professor Graham and Mottram, Professor Jeremy
Authors: Smith, B.O., Picken, N.C., Westrop, G.D., Bromek, K., Mottram, J.C., and Coombs, G.H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Journal of Biological Chemistry
Journal Abbr.:J Biol Chem.
Publisher:American Society for Biochemistry and Molecular Biology, Inc.
ISSN:0021-9258
ISSN (Online):1083-351X
Published Online:28 December 2005

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
297261Post-genomic analysis of cysteine protease function in Leishmania parasitesJeremy MottramMedical Research Council (MRC)G0000508Infection Immunity and Inflammation Life Sciences