Crystal structure analysis for the pathogenesis of thrombosis
| Project/Area Number |
23570155
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Research Field |
Structural biochemistry
|
|---|
| Research Institution | National Cardiovascular Center Research Institute |
|---|
Principal Investigator |
AKIYAMA Masashi 独立行政法人国立循環器病研究センター, 研究所, 室長 (30298179)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
KOKAME Koichi 独立行政法人国立循環器病研究センター, 研究所, 室長 (40270730)
TAKEDA Soichi 独立行政法人国立循環器病研究センター, 研究所, 室長 (80332279)
|
|---|
| Project Period (FY) |
2011 – 2013
|
| Project Status |
Completed (Fiscal Year 2013)
|
| Budget Amount *help |
¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2011: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
|
|---|
| Keywords | ADAMTS13 / von Willebrand因子 / 結晶構造 / 酵素動力学 / VWF / ずり応力 / プロテインS |
|---|
| Research Abstract |
A P475S polymorphism in the ADAMTS-13 gene causes an reduction in plasma VWF-cleaving activity. To demonstrate the impact of this mutation, we determined the crystal structure of the P475S mutant of ADAMTS13-DTCS (DTCS-P475S) and the enzymatic parameters of MDTCS-P475S. Structural analysis showed that the conformation of the V-loop was significantly different in DTCS-P475S, where no obvious interactions of Ser475 with other residues were observed. MDTCS-P475S showed a reaction rate similar to that of wild-type MDTCS, but showed two-fold lower affinity for the peptidyl substrate. MDTCS-P475S can moderately cleave shear-treated VWF. We have provided structural evidence that the P475S polymorphism in ADAMTS-13 leads to increased local structural instability, resulting in lowered affinity for the substrate without changing the reaction rate. The moderate activity of ADAMTS-13-P475S for shear-treated VWF is sufficient to prevent thrombotic thrombocytopenic purpura onset.
|
Report
(4 results)
Research Products
(18 results)
-
-
-
-
[Journal Article] ADAMTS13 safeguards the myocardium in a mouse model of acute myocardial infarction2012
Author(s)
Doi M, Matsui H, Takeda H, Saito Y, Takeda M, Matsunari Y, Nishio K, Shima M, Banno F, Akiyama M, Kokame K, Miyata T, Sugimoto M.
-
Journal Title
Thromb Haemost
Volume: 108
Pages: 1236-1238
Related Report
Peer Reviewed
-
-
-
-
[Journal Article] ADAMTS13 safeguards the myocardium in a mouse model of acute myocardial infarction.2012
Author(s)
Masaaki Doi, Hideto Matsui, Yukiji Takeda, Yoshihiko Saito, Maiko Takeda, Yasunori Matsunari, Kenji Nishio, Midori Shima, Fumiaki Banno, Masashi Akiyama, Koichi Kokame, Toshiyuki Miyata, and Mitsuhiko Sugimoto.
-
Journal Title
Thromb. Haemost.
Volume: 108
Issue: 12
Pages: 1236-1238
DOI
Related Report
Peer Reviewed
-
-
-
-
[Presentation] マウス急性心筋梗塞モデルにおけるADAMTS13の心筋保護作用2013
Author(s)
土井政明, 松井英人, 竹田征治, 斎藤能彦, 武田麻衣子, 松成泰典, 西尾健治, 嶋緑倫, 坂野史明, 秋山正志, 小亀浩市, 宮田敏行, 杉本充彦
Organizer
第35回日本血栓止血学会学術集会
Place of Presentation
山形市
Related Report
-
[Presentation] Protective role of ADAMTS13 for myocardium in mouse model of experimental myocardial infarction2012
Author(s)
Masaaki Doi, Hideto Matsui, Yukiji Takeda, Yoshihiko Saito, Maiko Takeda, Yasunori Matsunari, Kenji Nishio, Midori Shima, Fumiaki Banno, Masashi Akiyama, Koichi Kokame, Toshiyuki Miyata, Mitsuhiko Sugimoto.
Organizer
54th American Society of Hematology, Annual Meeting and Exposition
Place of Presentation
Atlanta, USA.
Related Report
-
[Presentation] ADAMTS13 improving the cell engraftment efficacy in mouse model of bone marrow transplantation2012
Author(s)
Hideto Matsui, Masaaki Doi, Yasunori Matsunari, Maiko Takeda, Kenji Nishio, Midori Shima, Kenji Soejima, Fumiaki Banno, Masashi Akiyama, Koichi Kokame, Toshiyuki Miyata, Mitsuhiko Sugimoto.
Organizer
54th American Society of Hematology, Annual Meeting and Exposition
Place of Presentation
Atlanta, USA
Related Report
-
-
-
-
