Structural, binding, and mutational features of A domains. (A-B) The A1 (A) and A3 (B) domains (cyan) in identical orientations bound to GPIbα (magenta) and collagen (silver), respectively. Disulfides are in yellow stick. (A) The A1-GPIbα complex forms a super β-sheet at the interface between the A1 β3 and GPIbα β14 strands. PT-VWD mutations (green Cα atom spheres) stabilize the β-switch in its bound over its unbound conformation.⁶⁸  VWD type 2B mutations (red Cα spheres)⁸³  locate distal from the GPIbα interface, near to the A2 termini where elongational force is applied. VWD type 2B mutations are hypothesized to stabilize an alternative, high-affinity conformation.^64,65,71  A region of GPIbα that is important for interaction with A1 in high shear and in ristocetin is shown in gray.^74,75  (B) A3 with collagen bound (silver) shown in identical orientation as A1 in (A) and with collagen-contacting residues shown in stick.⁷⁷  A nuclear magnetic resonance structure of A3 bound to fibrillar collagen⁷⁶  shows an identical binding site (collagen-perturbed residues shown with Cα atom spheres). (C) Detail of 2 superimposed A2 structures, 1 of which shows a 2 Å outward movement of the C-terminal α6-helix that may mimic an early step in elongational force-induced A2 unfolding. Arrows show direction of movement of key sidechains including scissile residue Tyr¹⁶⁰⁵ and α6-helix regions. C-terminal residue Ser¹⁶⁷¹ is labeled “C,” arrows show direction of movement from chain A to chain C.⁵¹  (D-E) VWD type 2M mutations^82,83  (silver Cα-atom spheres) in A1 (D) and A3 (E), shown in identical orientations. Type 2M mutations are much more numerous and widely distributed in A1. VWD type 2M mutations in A3 locate adjacent to or are buried beneath the collagen binding site. (F) A2 domain structural specializations. The view is rotated almost 180° from that in Figure 5B. Ca²⁺ is shown as a sphere with coordinating sidechain and backbone carbonyl groups in stick. Isomerization of the cis-peptide bond shown in stick would slow refolding. In C-F, A domain secondary structures are emphasized by their colors: β-strand, cyan; α-helix, magenta; loop, orange yellow. Collagen bound to A3 is shown in silver.