Location of solvent-exposed mutations on the FVIIIa surface. Solid surface representation of the 2 hypothesized quaternary arrangements of human FVIIIa, the “compact” (A) and “extended” models (B). Domains are labeled, and the distances from the phospholipid membrane are indicated (calculated as minimum distances between the C-terminal Cys residue in domain A1, Cys329, to a plane passing through Cα atoms of membrane-binding residues in C2, Met2199, Phe2200, and Leu2252). The side chains of 4 novel mutations affecting exposed residues, Pro64, Ala375, Gly494, and Asp2267, are represented as light magenta spheres. In addition, several residues previously reported to participate in VWF binding are highlighted as yellow spheres; other reported but not characterized mutations affecting exposed residues are in red. A curved arrow points to the probable displacement of C-terminal residues from the a1 linker to a more extended conformation after cleavage of the Arg372-Ser373 peptide bond. This would bring further residues implicated in FX binding (eg, the triplet of acidic residues Asp361/Asp362/Asp363; Nogami et al⁷ ) closer to the putative substrate binding site.