Prekallikrein and factor XI apple 4 domains. (A) Apple domain schematic. A typical apple (PAN) domain contains ∼90 amino acids (indicated by circles) and is constrained by 3 disulfide bonds (black circles and connecting bars). The region of the domain within the gray box is presented in detail in panels B and C. (B) PK-A4 residues 298 to 329. Amino acids from the PK-A4 domain highlighted by the gray box in panel A are shown for the coelacanth, West African lungfish, and human PK. Residues 321 and 326 are highlighted. In lungfish and human PK, these residues are cysteines that form a disulfide bond. In the coelacanth, they are histidine and phenylalanine. (C) FXI-A4 residues 298 to 329. Amino acids from the FXI-A4 domain highlighted by the gray box in panel A are shown for platypus, opossum, and human FXI. Residues 321 and 326 are highlighted. Residue 326 is glycine in all 3 species. In opossum and human FXI, residue 321 is a cysteine that forms the interchain disulfide bond connecting the subunits of the FXI dimer. (D) Topology diagrams of the human FXI dimer interface. Shown are 2 FXI-A4 domains (1 subunit is shown in yellow; the other in white) forming the FXI dimer interface. The Cys³²¹-Cys³²¹ interchain disulfide bond is shown at the top in orange. Hydrophobic residues Leu²⁸⁴, Ile²⁹⁰, and Tyr³²⁹ are shown in black, and salt bridges are formed between Lys³³¹ (blue) and Glu²⁸⁷ (red) and Arg³⁴⁵ (blue) and Asp²⁸⁹ (red). The bottom image is rotated 90° relative to the top image. After Papagrigoriou et al.⁵³  (E) Predicted FXI dimer interface for platypus FXI. Interactions are the same as those in panel D. The Cys³²¹-Cys³²¹ is not present in platypus FXI; instead, there is an additional salt bridge between Arg³²⁵ (blue) and Asp³²¹ (red). The bottom image is rotated 90° relative to the top image.