Human FXI apple domains. Topology diagrams based on the FXI zymogen structure. For all diagrams, the first, second, third, and fourth apple domains (A1, A2, A3, and A4) are shown in cyan, light blue, orange, and yellow, respectively. (A) The apple domain consists of a 7-stranded β-sheet (blue) with a central α-helix positioned on top (red). Disulfide bonds are shown in orange. (B) Topology diagram showing the disk formed by the 4 apple domains, with the catalytic domain removed. Sites of residues implicated in ligand binding are red for thrombin, green for high-molecular-weight kininogen (HK), black for GPIb, blue for heparin, and orange for FIX. (C) Apple domain disk showing the positions of mutations identified in FXI-deficient patients that involve buried residues (green) or surface exposed residues (red). Mutations Gly155Glu, Arg184Gly, and Ser248Asn (boxed) are examples of rare CRM⁺ mutations. (D) Two A4 domains forming the FXI dimer interface. The Cys321 interchain disulfide bond is shown at the top in orange. Hydrophobic residues Leu284, Ile290, and Tyr329 are shown in black, and a salt bridge is formed between Lys331 (blue) and Glu287 (red).