Biomedical Engineering Reference
In-Depth Information
a similar protein fold. A clan consists of two letters, the fi rst designating
the catalytic type, for example, C for cysteine while the second is a serial
letter. The term family describes a group of peptidases that are shown by
their primary structures to be evolutionary related and have a statistically
signifi cant relationship in their amino acid sequence. The family name
consists of the letter again indicating the catalytic type followed by a serial
number of up to two digits (Meslin et al. 2011, Rawlings 2010).
The activation of Cys-dependent Asp-specifi c peptidases are crucial for
most cell death pathways. Caspases (cysteinyl aspartate-specifi c proteases)
are cysteine proteases that cleave their substrates after an aspartate
residue and can be divided into two types based on their overall structure
and activation modes. Effectors or executioner caspases are activated by
proteolytic separation of the large (p20) and small (p10) subunits which
results in active (p20)2(p10)2 heterotetramers. Initiator caspases have an
N-terminal extension (the prodomain) which is required to incorporate
them into protein complexes that function as activation platforms, called
apoptosomes (Riedl and Salvesen 2007). Their activation is dependent upon
conformational changes after oligomerization but does not necessitate
proteolytic cleavage (Fuentes-Prior and Salvesen 2004). Initiator caspases
can ignite a cascade by the proteolytic activation of effector caspase
zymogens. The effector caspases cleave numerous substrates, producing
the characteristic features of apoptosis (Kumar 2006, Timmer and Salvesen
2006). Proteases from the CD family are characterized by their specifi city
for the P1 residue at the N-terminal side of the scissile bond. For caspases,
substrate recognition requires three or more residues, N terminal to P1-Asp.
Caspases are not only associated with apoptosis, they are also involved in
multiple vital roles ranging from immune regulation to spermatogenesis
(Carmona-Gutierrez et al. 2010).
In 2000, two novel caspase relatives were identifi ed in silico in plants,
fungi, and protozoa and were labelled metacaspases and paracaspases
(Uren et al. 2000). Paracaspases are involved in the development of
MALT lymphoma, but not in cell death execution, and are found both in
eukaryotes owning caspases (animals), as well as in organisms lacking
caspases (Carmona-Gutierrez et al. 2010). Paracaspases contain a prodomain
consisting of a death domain and one or two Ig domains. Paracaspases
contain a catalytic cysteine and histidine diad considered vital for activity.
Metacaspases are evolutionary distant orthologues of metazoan
caspases and seem to be restricted to fungi, plants and protozoa (Uren et
al. 2000). Metacaspases, like paracaspases, contain the catalytic Cys/His
diad considered vital for enzyme activity. Metacaspases have little sequence
specifi city to caspases but they do have similar secondary structure to
caspase-1 and caspase-3 (Carmona-Gutierrez et al. 2010, Uren et al. 2000).
