Structure of the C4 domain. (A) Three-dimensional representation of the VWF C4 domain derived from PDB-deposit 6FWN.83 The RGD motif is highlighted in red. SD1 and SD2 represent subdomains 1 and 2, respectively. Conserved disulfide bridges (1, 2, 3, and 5) are indicated in blue, and the C4-specific disulfide bridge (C4) is in green. Figure was generated using PyMOL software. (B) Provisional alignment (not at scale) of the RGD motif within the C4 domain (PDB-deposit 6FWN) with the RGD-binding pocket of αIIbβ3 (PDB-deposit 3ZDX). Figure was generated using PyMOL software. (C) Two-dimensional representation of the C4 domain. SD1 and SD2 refer to subdomains 1 and 2, respectively. Blue circles indicate disulfide bridges conserved among VWC domains, whereas green circles represent the disulfide bridge that is unique to the C4 domain. RGD motif is indicated with red circles. Squares indicate positions of residues where mutations have been associated with reduced αIIbβ3 binding in patients with von Willebrand disease-type 2M.
