Biomedical Engineering Reference
In-Depth Information
position 790 of the Asp-Ala-Val-Asp (DAVD) motif during apoptosis by
caspase-3 (Sundstrom et al. 2009). This data establishes similarities and,
equally, differences between caspases and metacaspases. Both cleave the
same substrate with a central role in the cell degradome and in both cases
this proteolytic event resulted in cell death. This provides evidence that
metacaspase could be involved in apoptosis control.
Nevertheless, the molecular patterns of
in vivo
TSN cleavage by
caspase-3 and metacaspase mcII-Pa are different. This demonstrates
dissimilar substrate specifi city of the two proteases both in terms of the
P1 residue (Asp versus Arg or Lys, correspondingly) and preferences for
specifi c residues at the P2, P3, and P4 positions (conservative versus liberal).
This indicates that proteases progressed more rapidly during the evolution
of the PCD machinery than their target proteins which resulted in the
partial preservation of the caspase and metacaspase degradomes. When an
effector caspase, caspase- 3, is compared with a type II metacaspase, mcII-
Pa, a number of signifi cant observations were identifi ed. It was established
that both proteases are crucial for development as well as PCD and have
some conserved features, including a common proteolytic target, TSN, in
the cell. However, Ca
2+
is required for activation of mcII-Pa, unlike that of
caspase-3 (and other caspases) (Sundstrom et al. 2009). It is yet to be fully
determined if such biochemical differences infl uence the physiological
functions of caspases and metacaspases.
The differences in the biochemical properties of metacaspases and
caspases have led to disagreements in the PCD arena. Some such as Frank
Madeo and colleagues support the assessment that metacaspases are
functionally equivalent to caspases (Carmona-Gutierrez et al. 2010) while
Guy Salvesen and associates believe otherwise (Enoksson and Salvesen
2010, Vercammen et al. 2007). It has been clearly established that these two
families of proteins are very similar in some circumstances for example
both cleave TSN during PCD and contain a caspase fold. However in many
situations they are very different. For example, as mentioned previously,
the P1 preference for metacaspases is basic while that of caspases is
acidic. In addition, caspases have not been implicated in the clearance
of protein aggregates (although this possibility cannot be excluded). To
add to this, a limited understanding of the molecular mechanisms of
metacaspase activation
in vivo
and metacaspase degradome impedes a
comprehensive comparison of their biochemical properties with those of
caspases (Bozhkov et al. 2010, Vercammen et al. 2007, Meslin et al. 2011).
Caspases and metacaspases, however, are evidently united in their
capability to accomplish multiple and often unrelated functions in the
eukaryotic cells.
