Plasma kallikrein (EC 3.4.21.34) and coagulation factor XI (EC 3.4.21.27) aretwo related plasma serine proteases activated by factor XIIA and which sharethe same domain topology: an N-terminal region that contains four tandemrepeats of about 90 amino acids and a C-terminal catalytic domain. The 90 amino-acid repeated domain contains 6 conserved cysteines. It has beenshown [1, 2] that three disulfide bonds link the first and sixth, second and fifth, and third and fourth cysteines. The domain can be drawn in the shape of an apple (see below) and has been accordingly called the 'apple domain'.
The apple domains of plasma prekallikrein are known to mediate its binding tohigh molecular weight kininogen [3], the apple domains of factor XI bind to factor XIIa, platelets, kininogen, factor IX and heparin [4].
The apple domains display some sequence similarity with the N domain ofplasminogen/hepatocyte growth factor (HGF) and to some nematode and protozoanproteins [5]. They all belong to the same domain superfamily that have been called the PAN module [6]. The N domain of hepatocyte growth factor binds to the c-Met receptor and to the heparin molecule. The structure of the PAN module of HGF has been solved. It contains a characteristichairpin-loop structure stabilised by two disulfide bridges, Cys-1 and 6 arenot conserved in HGF PAN modules [7].
Apart from the cysteines, there are a number of other conserved positions inthe apple domain. This entry represents the PAN domain of the plasma kalllikrein/coagulation factor XI subgroup proteins.
1. Location of the disulfide bonds in human plasma prekallikrein: the presence of four novel apple domains in the amino-terminal portion of the molecule. Biochemistry 30, 2050-6
2. Location of the disulfide bonds in human coagulation factor XI: the presence of tandem apple domains. Biochemistry 30, 2056-60
3. Mapping of the discontinuous kininogen binding site of prekallikrein. A distal binding segment is located in the heavy chain domain A4. J. Biol. Chem. 271, 13061-7
4. A binding site for heparin in the apple 3 domain of factor XI. J. Biol. Chem. 273, 16382-90
5. The PAN module: the N-terminal domains of plasminogen and hepatocyte growth factor are homologous with the apple domains of the prekallikrein family and with a novel domain found in numerous nematode proteins. FEBS Lett. 461, 63-7
6. Domains of invasion organelle proteins from apicomplexan parasites are homologous with the Apple domains of blood coagulation factor XI and plasma pre-kallikrein and are members of the PAN module superfamily. FEBS Lett. 497, 31-8
7. The solution structure of the N-terminal domain of hepatocyte growth factor reveals a potential heparin-binding site. Structure 6, 109-16
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