Major FVIII binding sequence on VWF. The amino-terminal 99 residues (residues 766-864) of the mature VWF protein comprise the TIL′ and E′ domains, which form the basis of this paper. Positionally conserved cysteine residues are highlighted in black and numbered sequentially. Yellow lines show disulfide connectivities, and an asterisk marks connectivities that have been previously chemically assigned. The circled Cys846-863 (2-6) disulfide connectivity of the E′ domain is assigned in this study. Type 2N VWD mutations are shown with arrows directly under the sequence together with the 1-letter code of the mutation; type 2N mutations involving a cysteine residue are in black, and noncysteine mutations are in green. Secondary structure elements (arrow, β sheet; line, loop; spiral, 3₁₀ helix) are shown under the sequence.