A novel calcium-binding site of von Willebrand factor A2 domain regulates its cleavage by ADAMTS13
文献类型：期刊论文
| 作者 | Zhou, MY; Dong, XC; Baldauf, C; Chen, H; Zhou, YF; Springer, TA; Luo, XP; Zhong, C; Grater, F; Ding, JP |
| 刊名 | BLOOD
 |
| 出版日期 | 2011 |
| 卷号 | 117期号:17页码:4623-4631 |
| 通讯作者 | Ding, JP (reprint author), 320 Yue Yang Rd, Shanghai 200031, Peoples R China.,jpding@sibs.ac.cn |
| 英文摘要 | The proteolysis of VWF by ADAMTS13 is an essential step in the regulation of its hemostatic and thrombogenic potential. Thecleavage occurs at strand beta 4 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 alpha 3-beta 4 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 alpha 3-beta 4 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 beta 4 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. (Blood. 2011;117(17):4623-4631) |
| 学科主题 | Hematology |
| 类目[WOS] | Hematology |
| 关键词[WOS] | VONWILLEBRAND-FACTOR ; CRYSTAL-STRUCTURE ; SHEAR-STRESS ; PROTEOLYSIS ; MUTATIONS ; DISEASE ; PLASMA ; MODEL ; THROMBOSIS ; SUBSTRATE |
| 收录类别 | SCI |
| 语种 | 英语 |
| WOS记录号 | WOS:000289984800028 |
| 版本 | 出版稿 |
| 源URL | [http://202.127.25.143/handle/331003/879]  |
| 专题 | 上海生化细胞研究所_上海生科院生化细胞研究所 |
| 推荐引用方式 GB/T 7714 | Zhou, MY,Dong, XC,Baldauf, C,et al. A novel calcium-binding site of von Willebrand factor A2 domain regulates its cleavage by ADAMTS13[J]. BLOOD,2011,117(17):4623-4631. |
| APA | Zhou, MY.,Dong, XC.,Baldauf, C.,Chen, H.,Zhou, YF.,...&Ding, JP.(2011).A novel calcium-binding site of von Willebrand factor A2 domain regulates its cleavage by ADAMTS13.BLOOD,117(17),4623-4631. |
| MLA | Zhou, MY,et al."A novel calcium-binding site of von Willebrand factor A2 domain regulates its cleavage by ADAMTS13".BLOOD 117.17(2011):4623-4631. |
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