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Figure 4.
ADAMTS13-VWF interactions. (A) Folded and unfolded structures
of the VWF A2 domain. The VWF A2 domain adopts a Rossman fold
with a central 6-stranded β-sheet surrounded by 5 α-helices
(shown as “A2 folded”) (28). The scissile peptide bond
(Tyr-1605-Met-1606) is buried within the protein core under
static conditions. The C-terminal region (residues
1,596–1,668, corresponding to VWF73) (31) of the A2 domain
must be unfolded to expose the scissile bond and the
exosite-binding regions under shear-stress conditions (shown as
A2 unfolded). (B) ADAMTS13-MDTCS-VWF binding model. The
molecular surface of the ADAMTS13-MDTCS model is shown in gray
and the bound zinc ion is shown in yellow. Residues that mediate
VWF binding are depicted as in Fig. 3C, and the exosites and the
catalytic cleft are indicated by red and yellow dotted
ellipsoids, respectively. The dotted green line represents a VWF
molecule (residues 1,596–1,668) bound to ADAMTS-MDTCS. (C)
Close-up view of the α6 helix and surrounding residues in the
VWF A2 domain. Hydrophobic residues are indicated with red
letters. Systematic charge-to-alanine substitutions revealed
that the D1653A and D1663A mutations (cyan) reduced the
substrate cleavage, the E1655A mutation (orange) slightly
increased cleavage, and the R1659A, E1660A, and R1668A mutations
(gray) had no significant effect (34).
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