Are metacaspases caspases?

Abstract

The identification of caspases as major regulators of apoptotic cell death in animals initiated a quest for homologous peptidases in other kingdoms. With the discovery of metacaspases in plants, fungi, and protozoa, this search had apparently reached its goal. However, there is compelling evidence that metacaspases lack caspase activity and that they are not responsible for the caspaselike activities detected during plant and fungal cell death. In this paper, we attempt to broaden the discussion of these peptidases to biological functions beyond apoptosis and cell death. We further suggest that metacaspases and paracaspases, although sharing structural and mechanistic features with the metazoan caspases, form a distinct family of clan CD cysteine peptidases.

Figure 1.

Structural properties of caspases, paracaspases, and metacaspases. (A) Schematic representation of the domains of caspases (C), metacaspases (MC), and paracaspases (PC). The catalytic domains consist of a large p20 (red) and small p10 subunit (green). Positions of the catalytic His and Cys residues are indicated by yellow bars. Prodomains of inflammatory and proapoptotic initiator caspases and type I metacaspases are in gray. The N-terminal domain of paracaspases contains a death domain (black) and one or two Ig domains (blue). The C-terminal region of paracaspases, which is involved in ubiquitination, is shown in pink. (B) Topological diagram of the structure of human caspase 8 and metacaspase 9 of Arabidopsis thaliana. Catalytic His and Cys residues are labeled in red, (putative) S1 pocket–forming residues are in blue, and maturation sites are in green. Figure layout is adapted from the diagram for human caspase 8 in Fuentes-Prior and Salvesen (2004). The secondary structure of AtMC9 was predicted using the Protein Structure Prediction Server (McGuffin et al., 2000).

Figure 2.

Phylogenic distribution of caspases, metacaspases, paracaspases, and bacterial para-/metacaspase-like proteins. C, caspase; MC, metacaspase; PC, paracaspase; protoPC/MC, bacterial para-/metacaspase-like proteins. Classification of cellular life into one prokaryotic (Bacteria, including Archaebacteria) and five eukaryotic kingdoms (Fungi, Protozoa, Chromista, Animalia, and Plantae) as described in Cavalier-Smith (2004). HGT events are indicated by dotted arrows.