Metacaspases

Abstract

Metacaspases are cysteine-dependent proteases found in protozoa, fungi and plants and are distantly related to metazoan caspases. Although metacaspases share structural properties with those of caspases, they lack Asp specificity and cleave their targets after Arg or Lys residues. Studies performed over the past 10 years have demonstrated that metacaspases are multifunctional proteases essential for normal physiology of non-metazoan organisms. This article provides a comprehensive overview of the metacaspase function and molecular regulation during programmed cell death, stress and cell proliferation, as well as an analysis of the first metacaspase-mediated proteolytic pathway. To prevent further misapplication of caspase-specific molecular probes for measuring and inhibiting metacaspase activity, we provide a list of probes suitable for metacaspases.

Figure 1

Distribution of type I and II metacaspases within plant genomes

Figure 2

The mechanisms of TSN cleavage during cell death. (a) Domain structure of TSN, and location of metacaspase and caspase cleavage sites. (b and c) Structural preferences for the cleavage of TSN by caspase-3 and metacaspase mcII-Pa. (b) Caspase-3 cleaves helix α2 of human TSN. Tudor-SN5 part of human TSN is shown as cartoon with the SN5 and Tudor domains painted in cyan and pink, respectively. The caspase-3 cleavage motif (787-DAVD-790) is located in the middle of helix α2. Three of four residues of the motif, Asp 787 and 790 and Val 789 are accessible to the solvent. The α2 helix exposes six Asp residues (including two Asp residue of the DAVD motif; shown in spheres), creating a highly negatively charged patch on the surface of the helix. The abundance of Asp residues around the cleavage site might facilitate its recognition by caspase-3. (c) Metacaspase mcII-Pa cleaves a structured but solvent accessible loop (α2-β8) of the SN2 domain (cartoon painted in rainbow) of spruce TSN. The loop is cleaved after Arg 287 (shown in spheres). The structure of the SN2 domain of spruce TSN was modeled with SwissModel using staphylococcal nuclease (PDB 1SNC) and Tudor-SN5 part of human TSN (PDB 2O4X) as template structures. Arrows in b and c indicate cleavage sites. Graphics was generated using PyMol. (d) A proposed model for pro-cell death role of metacaspase-mediated cleavage of TSN. Mc, metacaspases