Metacaspases

Tsiatsiani, Liana; Breusegem, Frank Van; Gallois, Patrick; Zavialov, Anton V.; Lam, Eric; Bozhkov, Peter V.

doi:10.1038/cdd.2011.66

Cited by 299 publications

(334 citation statements)

References 73 publications

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“…[16][17][18]28 All metacaspases studied so far are strictly specific for basic amino-acid residues at P1 position when using either synthetic peptides or protein as substrates. 9,22,29 However, significant differences were found when studying if protein maturation was required for activity.…”

Section: Discussionmentioning

confidence: 99%

“…6 Evidences suggest that metacaspases modulate cell death, [7][8][9][10][11] cell cycle progression [12][13][14] and protein aggregation, 15 but there is still controversy about their functions and their relation with caspases. [16][17][18] The fact that metacaspases are not present in humans and fulfil important roles in trypanosomatids make them attractive drug targets, and a first series of inhibitors with trypanocidal activity has been developed recently. 19 Trypanosomatid metacaspases can be distinguished by their overall domain composition and gene copy number.…”

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Antagonic activities of Trypanosoma cruzi metacaspases affect the balance between cell proliferation, death and differentiation

2012

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Metacaspases are distant relatives of animal caspases present in plants, fungi and protozoa. At variance with caspases, metacaspases exhibit stringent specificity for basic amino-acid residues and are absolutely dependent on millimolar concentrations of calcium. In the protozoan parasite Trypanosoma cruzi, metacaspases have been suggested to be involved in an apoptosis-like phenomenon upon exposure of the parasite to fresh human serum (FHS). Nuclear relocalization of metacaspases was observed after FHS treatment and overexpression of metacaspase-5 led to enhanced sensitivity to this stimulus. Here we report some biochemical properties of T. cruzi metacaspases. Performing fluorescent-activated cell sorting (FACS) analysis of epimastigotes inducibly overexpressing metacaspase-3, we demonstrate a role for this metacaspase in cell cycle progression, protection of epimastigotes from naturally occurring cell death and differentiation to infective metacyclic trypomastigotes. We also show that regulation of metacaspase-3 activity is important for cell cycle completion inside the mammalian host. On the other hand, inducible overexpression of metacaspase-5 lacking its C-terminal domain caused an apoptotic-like response. These results suggest that the two T. cruzi metacaspases could play an important role in the life cycle and bring to light the close relationship between cell division, death and differentiation in this ancient unicellular eukaryote.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Antagonic activities of Trypanosoma cruzi metacaspases affect the balance between cell proliferation, death and differentiation

2012

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“…One, Tudor staphylococcal nuclease, a substrate for mcII-Pa metacaspase in the Norway spruce, Picea abies, is also a substrate for human caspase-3, and this has been taken as indicating a level of evolutionary conservation between PCD pathways (16). It is now apparent, however, that metacaspases have a variety of cellular functions that are distinct from those of the caspases, which may reflect the distinct differences in substrate specificity and activation (11). For example, in yeast, the Yca1 metacaspase is required for clearance of cellular protein aggregates as well as regulation of the timing of the cell cycle, a function that has also been identified in the parasitic protozoon Leishmania (9,(17)(18)(19).…”

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confidence: 99%

“…Various attempts have been made to draw parallels between caspases and metacaspases in respect to structure, activation, and function (11). However, two striking differences between metacaspases and caspases are their substrate specificities and requirements for activation.…”

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confidence: 99%

Crystal structure of a Trypanosoma brucei metacaspase

McLuskey

Rudolf

Proto

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

110

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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.apoptosis | clan CD | parasite | X-ray crystallography P rogrammed cell death (PCD) is essential for animal development and the maintenance of adult tissues. PCD itself is a regulated process, and in animals, apoptosis is controlled through the action of caspases, aspartic acid-specific cysteine peptidases (1). PCD is also essential for plant development (2), and multiple markers for apoptosis have been described in yeast and a broad range of protozoan parasites (3), yet these organisms do not encode caspases in their genomes; thus, alternative pathways must have evolved for caspase-independent cell death to be regulated. In recent years, attention has focused on the metacaspases, which are a highly conserved group of caspase-like cysteine peptidases found in plants, fungi, and protozoa but not in the metazoa (4). In plants, metacaspases are essential for embryogenesis (5, 6) and have been shown to act in antagonistic relationships, functioning as both positive and negative regulators of PCD (7). In yeast and some protozoa, metacaspases have been implicated as mediators of cell death in response to oxidative stress and environmental change (3,(8)(9)(10).Various attempts have been made to draw parallels between caspases and metacaspases in respect to structure, activation, and function (11). However, two striking differences between metacaspases and caspases are their substrate specificities and requirements for activation. Metacaspases have arginine/lysine specificity, do not necessarily require proces...

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“…Among these proteases, metacaspases are the closest relatives and putative ancestors of caspases. Tsiatsiani et al 19 illuminate different aspects of metacaspase biology, stretching the scope beyond cell death to include emerging roles of metacaspases in cell proliferation and stress response. Critical analysis of substrate specificity and other biochemical properties of metacaspases is connected to the practical recommendations on how to measure and inhibit metacaspase activity by taking into account their arginine/ lysine specificity.…”

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confidence: 99%