3PPX
Crystal structure of the N1602A mutant of an engineered VWF A2 domain (N1493C and C1670S)
Summary for 3PPX
| Entry DOI | 10.2210/pdb3ppx/pdb |
| Related | 3GXB 3PPV 3PPW 3PPY |
| Descriptor | von Willebrand factor, SODIUM ION (3 entities in total) |
| Functional Keywords | von willebrand factor, vwa domain, rossmann fold, blood coagulation, cell adhesion, protein unfolding, adamts13 cleavage, glycosylation |
| Biological source | Homo sapiens (human) |
| Cellular location | Secreted : P04275 |
| Total number of polymer chains | 1 |
| Total formula weight | 22043.79 |
| Authors | |
| Primary citation | Zhou, M.,Dong, X.,Baldauf, C.,Chen, H.,Zhou, Y.,Springer, T.A.,Luo, X.,Zhong, C.,Grater, F.,Ding, J. A novel calcium-binding site of von Willebrand factor A2 domain regulates its cleavage by ADAMTS13 Blood, 117:4623-4631, 2011 Cited by PubMed Abstract: The proteolysis of VWF by ADAMTS13 is an essential step in the regulation of its hemostatic and thrombogenic potential. The cleavage occurs at strand β4 in the structural core of the A2 domain of VWF, so unfolding of the A2 domain is a prerequisite for cleavage. In the present study, we present the crystal structure of an engineered A2 domain that exhibits a significant difference in the α3-β4 loop compared with the previously reported structure of wild-type A2. Intriguingly, a metal ion was detected at a site formed mainly by the C-terminal region of the α3-β4 loop that was later identified as Ca(²+) after various biophysical and biochemical studies. Force-probe molecular dynamic simulations of a modeled structure of the wild-type A2 featuring the discovered Ca(²+)-binding site revealed that an increase in force was needed to unfold strand β4 when Ca(²+) was bound. Cleavage assays consistently demonstrated that Ca(²+) binding stabilized the A2 domain and impeded its unfolding, and consequently protected it from cleavage by ADAMTS13. We have revealed a novel Ca(²+)-binding site at the A2 domain of VWF and demonstrated a relationship between Ca(²+) and force in the regulation of VWF and primary hemostasis. PubMed: 21385852DOI: 10.1182/blood-2010-11-321596 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.91 Å) |
Structure validation
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