Biomedical Engineering Reference
In-Depth Information
Sequence Alignments of Caspases, Paracaspases and
Metacaspases
The P1 preference of clan CD proteases is prescribed by the presence
of amino acids which are dispersed through the mature protease that
collectively form the S1 pocket. The basic S1 pocket is formed by Arg
179
,
Gln
283
, and Arg
341
(according to caspase-1 residue numbering) for optimal
binding of the acidic P1-Asp within their substrates (Fuentes-Prior and
Salvesen 2004). The available sequences of eukaryotic metacaspases,
paracaspases and bacterial meta/paracaspase homologues were aligned
and compared with animal caspase sequences. It was established that
Gln
283
is replaced by an Asp, Arg
179
of caspases aligns to Leu and Arg
341
is
replaced by Asp or Glu in both para- and metacaspases. Six residues more
C terminal, a highly conserved Asp is present that aligns with Asp
163
of
bacterial gingipain R, which is known to synchronize binding of the P1-
Arg of substrates of this peptidase (Eichinger et al. 1999). These residues
combined are perfectly positioned to generate a highly acidic S1 pocket
that is suited to receive the basic P1 residues Arg and Lys. The Arg/Lys
specifi city is very probably shared by all para- and metacaspases as the
S1 pocket-forming residues are preserved in all known sequences. The P1
specifi city of metacaspases of other plants, yeast and protozoa have been
determined and have confi rmed this theory. At present, no close bacterial
caspase homologues have, as yet, been identifi ed. This indicates an animal-
specifi c evolutionary process of gene duplications and progression of
the caspases from Arg/Lys toward Asp specifi city (Bozhkov et al. 2010,
Watanabe and Lam 2005).
Apoptosis
To understand the role of metacaspases in apoptosis, we feel it necessary to
fi rst review the key processes of apoptosis. The term apoptosis is used to
describe a morphologically distinct form of programmed cell death (PCD)
(Collins et al. 1992). PCD is a highly conserved cellular suicide program
which has been described and studied in great detail in multicellular
organisms. Although apoptosis is mainly recognized for its developmental
roles in higher eukaryotes, it is not restricted to metazoans, it appears to
occur in most living systems. Over the past decade evidence of PCD has
been exposed in both yeast and fi lamentous fungi. (Lewis 2000, Golstein
et al. 2003, Lu 2006, Ramsdale 2006, Robson 2006).
Two main categories of PCD have been characterized. These are
apoptosis and autophagy. The main features of apoptosis (type I PCD) are
externalization of phosphatidylserine, the accumulation of DNA-strand
