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.