Crystal structure of a Trypanosoma brucei metacaspase

McLuskey, K., Rudolf, J., Proto, W. R., Isaacs, N. W., Coombs, G. H., Moss, C. X. and Mottram, J. C. (2012) Crystal structure of a Trypanosoma brucei metacaspase. Proceedings of the National Academy of Sciences of the United States of America, 109(19), pp. 7469-7474. (doi:10.1073/pnas.1200885109)

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Publisher's URL: http://dx.doi.org/10.1073/pnas.1200885109

Abstract

Metacaspases are distantly related caspase-family cysteine peptidases implicated in programmed cell death in plants and lower eukaryotes. They differ significantly from caspases because they are calcium-activated, arginine-specific peptidases that do not require processing or dimerization for activity. To elucidate the basis of these differences and to determine the impact they might have on the control of cell death pathways in lower eukaryotes, the previously undescribed crystal structure of a metacaspase, an inactive mutant of metacaspase 2 (MCA2) from Trypanosoma brucei, has been determined to a resolution of 1.4 Å. The structure comprises a core caspase fold, but with an unusual eight-stranded β-sheet that stabilizes the protein as a monomer. Essential aspartic acid residues, in the predicted S1 binding pocket, delineate the arginine-specific substrate specificity. In addition, MCA2 possesses an unusual N terminus, which encircles the protein and traverses the catalytic dyad, with Y31 acting as a gatekeeper residue. The calcium-binding site is defined by samarium coordinated by four aspartic acid residues, whereas calcium binding itself induces an allosteric conformational change that could stabilize the active site in a fashion analogous to subunit processing in caspases. Collectively, these data give insights into the mechanistic basis of substrate specificity and mode of activation of MCA2 and provide a detailed framework for understanding the role of metacaspases in cell death pathways of lower eukaryotes.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Rudolf, Dr Jana and Proto, Mr William and Coombs, Professor Graham and McLuskey, Dr Karen and Moss, Dr Catherine and Isaacs, Professor Neil and Mottram, Professor Jeremy
Authors: McLuskey, K., Rudolf, J., Proto, W. R., Isaacs, N. W., Coombs, G. H., Moss, C. X., and Mottram, J. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
536341Structure and activity of trypanosomatid metacaspasesJeremy MottramWellcome Trust (WELLCOME)091790/Z/10/ZInfection Immunity and Inflammation Life Sciences
454141Analysing the roles of petidases in Leishmania infectivity and pathogenicityJeremy MottramMedical Research Council (MRC)G0700127Infection Immunity and Inflammation Life Sciences
371793The Wellcome Centre for Molecular Parasitology ( Core Support )J BarryWellcome Trust (WELLCOME)073990/Z/03/BInfection Immunity and Inflammation Life Sciences