Norman's paper on the Molecular interplay of ADAMTS13-MDTCS and von willebrand Factor-A2: deepened insights from extensive atomistic simulations is published
Transition morphing between Model2 (precursor) and active proteolytcic state Model1.
Graphical abstract showing final binding mode and conformational change in MP active site.
Figure 6. Overview of the interplay between VWF and ADAMTS13 and suggested activation mechanism. (a) In normal circulation, ADAMTS13 exists in a closed and inactive conformation (global latency). VWF multimers are self-folded to prevent unwanted interactions of the VWF-A1 domain with platelets. (b) In case of blood vessel damage, VWF-A3 domains bind to exposed subendothelial collagen, and the shear stress unpacks the VWF multimers into an extended chain. Platelets can then be recruited to the damaged vessel site, and this increases the shear forces on the VWF-A2 domain further. The A2 domain completely unfolds into a linear peptide strand and exposes the binding sites for ADAMTS13 and thus, the cryptic cleavage site. (c) The CUB domains of ADAMTS13 bind to the D4-CK domain of VWF (1) and get released from the Spacer domain (2). The Spacer (3) and Cys-rich (4) domains bind their precursor exosites on the unraveled A2 domain and thereby, guide the further association. The Dis domain binds a shifted A2-exosite around D1619 (5). Binding of D1614 to the calcium ion near the active site cleft allows the transition to the MP domain (6). The A2 strand binds the MP domain in a precursor state, not ready for cleavage (7). (d) The A2 strand is shifted towards the TSP1 domain from both ends (8) and the Dis, Cys-rich and Spacer domains bind their final target sites. The A2-strand is pulled through the gatekeeper tetrad and causes an allosteric change (9) that opens the active center (local latency). The MP domain can ultimately lock to the A2-cleavage site and cut the peptide strand.
Figure 4. (Top) Binding configuration of VWF-A2 across ADAMTS13-MDTCS domains, showing the proposed proteolytic binding state (Model1). A helical loop motif of A2 at the MP domain is prominent. (a) Zoom into the active site region of MP, showing VWF-A2 side chains (sticks) binding into various pockets on the MP surface. Both are colored by the average number of contacts, emphasizing the strength of contacts or their quantity. Important positions are labeled in orange for the MP domain and black for the A2 strand. The crossing to the neighboring Dis domain (orange cartoon) and characteristic binding of D1614 and R349 can be appreciated. (b) Precursor configuration at the MP domain (Model2), where D1614 binds the calcium ion next to the active site cleft and A2 shifts by roughly 5 amino acids towards the N-terminal. (c) Strongly shifted binding in opposite direction observed during precursor stage on the Cys-rich and Spacer domains. (Bottom) Interaction network of ADAMST13-MDTCS domains and VWF-A2 for the final proteolytic binding stage and contacts with affinities of 0.5 and larger (see Supporting Information for complete networks). VWF- A2 nodes are colored gray, while ADAMTS13 nodes are colored according to their domain with MP (red), Dis (orange), TSP1 (green), Cys-rich (purple) and Spacer (pink). Connection line thicknesses are linearly weighed by affinities of contacts and colored on the same scale from red to white for high and low affinity values, respectively.
Modern replica-exchange simulations with TIGER2h to sample the vast configurational space of ADAMTS13-MDTCS and the exposure to its substrate and activating cofactor – the unraveled VWF-A2 domain ...
Norman's paper named "Molecular interplay of ADAMTS13-MDTCS and von willebrand Factor-A2: deepened insights from extensive atomistic simulations" is published in the Journal of Biomolecular Structure and Dynamics. Congratulations Norman!
