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( F12 ; 5q33-qter) and urokinase ( PLAU ; 10q24-qter) exhibit similar gene organi-
zation with respect to their protease domains but differ from prothrombin ( F2 ;
11p11-q12) and factors VII, IX, X, and protein C. Kringle domains are encoded
by a similar gene structure wherever they occur, as are the calcium-binding Gla
domains. EGF-like domains are encoded by a single exon with type 1 splice junc-
tions as are the fibronectin type I (Fn I) domains.
The presence/absence of different modules (Gla and EGF-like domains,
kringles) in the different coagulation factor proteins can be used to reconstruct
their evolutionary past. The transfer of modules between proteins has arisen via
exon shuffling and protein data can be used to construct evolutionary trees
(Patthy, 1985) that are consistent with what is already known of the genes in terms
of their exon size and distribution. Patthy (1990) has described at length the prin-
ciples underlying the assembly of present-day coagulation factor genes from their
constituent modules. Evolution of these genes has proceeded by repeated inser-
tions, duplications, exchanges and deletions of modules. How has it been possible
to produce such a plethora of different proteins/genes by exon shuffling in what
has been a comparatively short period of evolutionary time? The answer appears
to lie firstly with the close correspondence between exon boundaries and the mod-
ular domains of the proteins and secondly with the fact that the ancestors of the
kringle, fibronectin, growth factor, protease and Gla modules all had phase 1
introns at both module boundaries.
The phylogenetic tree of the serine proteases, constructed by Patthy (1990) is
shown in Figure 3.9 . In this diagram, the major division between the blood coagu-
lation proteases and those involved in fibrinolysis is very apparent. This division
Ca 2+
binding
Signal
EGF-like
Protease
Factor VII
Factor IX
Factor X
Protein C
I
0
I
I
I
0
I
Ca 2+
binding
Kringle
Kringle
I
0
I
I
II
I
I
I
II
II
II
I
0
Prothrombin
Repeat 1
Repeat 2
Repeat 3
Repeat 4
I
II
I
II
I
II
I
II
I
II
I
I
0
Factor XI
EGF-
like
EGF-
like
Fn II
Fn I
Kringle
0
I
II
I
I
I
I
II
I
II
I
I
0
Factor XII
EGF-
like
Fn I
Kringle
Kringle
Tissue
plasminogen
activator
0
I
I
I
II
I
II
I
II
I
I
0
EGF-
like
Kringle
0
I
I
II
I
II
I
I
0
Urokinase
Figure 3.8. Organization of the genes of hemostatic proteins (redrawn from Tuddenham
and Cooper, 1994). Fn: Fibronectin-like domain. Intron phase is denoted by O, I or II.
 
 
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