The factor VIII molecule and its fatty feet. The complete FVIII molecule in the center is derived from the PDB entry 2R7E. The top part represents the 3 A domains (gray). The C1 and C2 domains are depicted in cyan blue and orange, respectively, and the lipid binding amino acids are depicted in red. The right panels show close-ups of the bottom of the C2 domain of factors VIII and V. The swapped residues are Met²¹⁹⁹/Phe²²⁰⁰ (right) and Leu²²⁵¹/Leu²²⁵² (left) in FVIII and Trp²⁰⁶³/Trp²⁰⁶⁴ (right) and Leu²¹¹⁶/Ser²¹¹⁷ (left) in FV. The left panels display the bottom of the C1 domain, with the Lys²⁰⁹²/Phe²⁰⁹³ foot of FVIII and its homologue Tyr¹⁹⁵⁶/Leu¹⁹⁵⁷ in FV. FV loops in the C2 domain are derived from PDB entry 1CZT, and those of the C1 domain by modeling the human sequence on the bovine template (entry 1SDD). These structures suggest that the 2 C domains stand side-by-side on the membrane and contribute in a cooperative manner to membrane binding. Because the C2 domain is only loosely attached in the structure by only few interdomain contacts, it may be capable of some reorientation in response to changes in the fatty feet or in the composition of the procoagulant membrane.