Figure 4.

Structural basis for pH-dependent VWF tubule formation. (A) The Cα positions of the 33 histidine residues resolved in the structure are depicted as spheres color-coded based on sequence conservation obtained from 140 homologs using the ConSurf server.⁴⁷ (B) Details of the intramonomer salt bridge made by H395. (C) Details of the intramonomer salt bridge made by H817. (D) Interface between D2-D3 of one molecule (denoted D2-1 and D3-1; gray) and the D2 domain of another molecule (D2-2; teal) (top). The interfaces are separated and colored by electrostatic potential calculated at pH 7.4 (middle) and 5.2 (bottom). Electrostatic potentials were calculated using default coulombic parameters in ChimeraX 1.3.²⁴ The positions of surface-exposed histidine residues are marked with a black circle or a yellow star if highlighted in panels (E-G). (E-G) Examples of histidine residues—(E) H421, (F) H556 and H817, and (G) H460—that change protonation state upon pH change from 7.4 to 5.2 in electronegative local environments.