PROSITE documentation PDOC00376
PAN/apple domain signature and profile


Plasma kallikrein (EC and coagulation factor XI (EC 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
                     .....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.

Last update:

May 2004 / Text revised.


Technical section

PROSITE methods (with tools and information) covered by this documentation:

PAN, PS50948; PAN/Apple domain profile  (MATRIX)

APPLE, PS00495; Apple domain  (PATTERN)


1AuthorsMcMullen B.A. Fujikawa K. Davie E.W.
TitleLocation of the disulfide bonds in human plasma prekallikrein: the presence of four novel apple domains in the amino-terminal portion of the molecule.
SourceBiochemistry 30:2050-2056(1991).
PubMed ID1998666

2AuthorsMcMullen B.A. Fujikawa K. Davie E.W.
TitleLocation of the disulfide bonds in human coagulation factor XI: the presence of tandem apple domains.
SourceBiochemistry 30:2056-2060(1991).
PubMed ID1998667

3AuthorsHerwald H. Renne T. Meijers J.C. Chung D.W. Page J.D. Colman R.W. Muller-Esterl W.
TitleMapping of the discontinuous kininogen binding site of prekallikrein. A distal binding segment is located in the heavy chain domain A4.
SourceJ. Biol. Chem. 271:13061-13067(1996).
PubMed ID8662705

4AuthorsHo D.H. Badellino K. Baglia F.A. Walsh P.N.
TitleA binding site for heparin in the apple 3 domain of factor XI.
SourceJ. Biol. Chem. 273:16382-16390(1998).
PubMed ID9632702

5AuthorsTordai H. Banyai L. Patthy L.
TitleThe 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.
SourceFEBS Lett. 461:63-67(1999).
PubMed ID10561497

6AuthorsBrown P.J. Gill A.C. Nugent P.G. McVey J.H. Tomley F.M.
TitleDomains 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.
SourceFEBS Lett. 497:31-38(2001).
PubMed ID11376658

7AuthorsZhou H. Mazzulla M.J. Kaufman J.D. Stahl S.J. Wingfield P.T. Rubin J.S. Bottaro D.P. Byrd R.A.
TitleThe solution structure of the N-terminal domain of hepatocyte growth factor reveals a potential heparin-binding site.
SourceStructure 6:109-116(1998).
PubMed ID9493272

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