PROSITE documentation PDOC00376

PAN/apple domain signature and profile

Plasma kallikrein (EC 3.4.21.34) and coagulation factor XI (EC 3.4.21.27) are two related plasma serine proteases activated by factor XIIA and which share the same domain topology: an N-terminal region that contains four tandem repeats of about 90 amino acids and a C-terminal catalytic domain.

The 90 amino-acid repeated domain contains 6 conserved cysteines. It has been shown [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'.

                      x x x     x x x
                    x      C---C      x
                   x      x     x      x
                  x       Cx x  x       x
                  x       |  x  x       x       Schematic representation of an
                  x       Cx x  x       x       apple domain.
                   x      x     x      x
                    x     x     x     x
                     x     x x x     x
                      x             x
                        x x     x x
                           C---C
                     .....x     x.....

The apple domains of plasma prekallikrein are known to mediate its binding to high molecular weight kininogen [3], the apple domains of factor XI bind to factor XIIa, platelets, kininogen, factor IX and heparin [4].

The apple domain display some sequence similarity with the N domain of plasminogen/hepatocyte growth factor (HGF) and to some nematode and protozoan proteins [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 (see <PDB:2HGF>). It contains a characteristic hairpin-loop structure stabilized by two disulfide bridges, Cys-1 and 6 are not conserved in HGF PAN modules [7].

Apart from the cysteines, there are a number of other conserved positions in the apple domain. We have developed a pattern, that spans the complete apple domain, and which includes these conserved positions. The pattern is specific to the plasma kalllikrein/coagulation factor XI subgroup. We also developed a profile that recognized all members of the PAN module superfamily and covers the whole domain.