Blood, 15 February 2002, Vol. 99, No. 4, pp. 1101-1101
Novel FVIII model: breakthrough and perspectives
Stoilova-McPhie and colleagues (page 1215)
present here an advanced study of the 3dimensional
structure of coagulation factor VIII (FVIII) bound to
phospholipid membrane. Previously, the crystal structure had
been obtained only for the C2 domain of FVIII, and structures of its A
domains had been proposed based on the homologous modeling. In their
breakthrough study, the authors obtained a novel model of
physiologically relevant complex of FVIII with phospholipid. The model
was built by fitting all accumulated structural data on FVIII domains
and positions of functionally important FVIII sites into an
electron-density map of 2-dimensional FVIII crystals assembled on
the surface of phospholipid vesicles. This model allowed refining
the relative position of FVIII domains and their positioning toward the
phospholipid surface and building a model of membrane-assembled
FVIII-factor IX complex (intrinsic Xase).
The presented noncontradictory model is definitely a step forward in
understanding structure-function relationships within the Xase complex.
In particular, this model reconciles the earlier data regarding
involvement of the C-terminal portion of the C2 domain (residues
2303-2332) in phospholipid binding with the recent finding that 2 hydrophobic feet within the N-terminal portion of C2 (residues
2199/2200 and 2251/2252) are major contributors to this binding.
Although some conclusions based on the analysis of the
C2-phospholipid interface in previous studies and the current
study have been proven by mutational analysis of FVIII, it remains to be identified which residues of the C2 domain additionally contribute to the energy of FVIII-phospholipid interaction. The presented model
can be also useful for interpretation of the recent finding that the C2
domain mediates FVIII interaction with factor IXa. It is likely that
further refinement of the Xase structure based on crystal studies with
higher resolution and modeling will lead to a more comprehensive
understanding of 3-dimensional organization and functioning of
the intrinsic Xase complex.
Evgueni Saenko
American Red Cross
