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bond but not at the Tyr4-Ile5 bond. Thus the relatively narrow specificity of the
primate
-chymase represents the ancestral state of the enzyme while the broader
specificity of the rat
-chymase must have been secondarily derived.
10.2 Molecular reconstruction and homology modelling of
the catalytic domain of the common ancestor of the
hemostatic vitamin K-dependent serine proteases
Adopting the maximum parsimony principle and employing a novel cDNA-based
strategy, Krawczak
et al
. (1996) reconstructed the catalytic domains of the early
mammalian ancestors of the vitamin K-dependent factors and then went on to
reconstruct the putative common ancestor of all five proteins from an earlier stage
of vertebrate evolution. A tertiary model of the ancestral vitamin K-dependent
serine protease was built that was both energetically satisfactory and possessed a
credible fold, and its topological and biophysical properties were examined.
Wacey
et al
. (1997) then traced the evolution of specific structural features in pro-
tein C from the common ancestor of the vitamin K-dependent serine proteases
toward extant human protein C. These studies will now be described in some
detail since they serve to illustrate the potential value of homology modelling in
evolutionary studies.
10.2.1 The evolution of the vitamin K-dependent coagulation factors
The vitamin K-dependent serine proteases of coagulation (factors VII, IX, and X,
prothrombin and protein C) exhibit substantial sequence and structural homol-
ogy (Greer, 1990). Factors VII, IX, X and protein C all contain an N-terminal
domain of glutamic acid (Gla) residues, two epidermal growth factor-like (EGF)
domains and a catalytic domain (Blake
et al.
, 1987); prothrombin differs slightly
in that it possesses two kringle domains instead of the EGF domains (Gojobori
and Ikeo, 1994). With the exception of prothrombin, the genes encoding the vita-
min K-dependent coagulation factors have a very similar exon/intron organiza-
tion (Tuddenham and Cooper, 1994), suggesting that they have arisen from a
relatively recent common ancestor through a process of gene duplication and
divergence (Neurath, 1984; Patthy, 1985; Patthy, 1990). The organization of these
genes also reflects the functional modular assembly of the respective proteins and
is thought to have emerged through exon shuffling (Chapter 3 section 3.6).
Evolution of these genes has proceeded by repeated insertions, duplications,
exchanges and deletions of modules. The presence/absence of modules such as the
calcium-binding Gla domains, the EGF-like domains and kringles was used by
Patthy (1990) to reconstruct the evolutionary past of the genes (
Figure 10.1
). More
recently, it has been realised, however, that each module or domain has its own
distinctive evolutionary history as a result of different evolutionary pressures
(Ikeo
et al
., 1995).
Doolittle (1993) also proposed a tentative scheme for the evolution of the vita-
min K-dependent coagulation factors (
Figure 10.1
). First, an ancestral prothrom-
bin emerged by serine protease gene duplication and the acquisition of Gla and
