Structural Basis for Sequential Cleavage of Fibrinopeptides upon Fibrin Assembly
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- 作者：Igor Pechik ; Sergiy Yakovlev ; Michael W. Mosesson ; Gary L. Gilliland ; and Leonid Medved
- 刊名：Biochemistry
- 出版年：2006
- 出版时间：March 21, 2006
- 年：2006
- 卷：45
- 期：11
- 页码：3588 - 3597
- 全文大小：1068K
- 年卷期：v.45,no.11(March 21, 2006)
- ISSN：1520-4995
文摘
Nonsubstrate interaction of thrombin with fibrinogen promotes sequential cleavage offibrinopeptides A and B (fpA and fpB, respectively) from the latter, resulting in its conversion into fibrin.The recently established crystal structure of human thrombin in complex with the central part of humanfibrin clarified the mechanism of this interaction. Here, we reveal new details of the structure and presentthe results of molecular modeling of the fpA- and fpB-containing portions of the A
rs/alpha.gif" BORDER=0> and Brs/beta2.gif" BORDER=0 ALIGN="middle"> chains, notidentified in the complex, in both fibrinogen and protofibrils. The analysis of the results reveals that infibrinogen the fpA-containing portions are in a more favorable position to bind in the active site cleft ofbound thrombin. Surface plasmon resonance experiments establish that the fpB-containing portions interactwith the fibrin-derived dimeric D-D fragment, suggesting that in protofibrils they bind to the newly formedDD regions bringing fpB into the vicinity of bound thrombin. These findings provide a coherent rationalefor the preferential removal of fpA from fibrinogen at the first stage of fibrin assembly and the acceleratedcleavage of fpB from protofibrils and/or fibrils at the second stage.
rs/alpha.gif" BORDER=0> and Brs/beta2.gif" BORDER=0 ALIGN="middle"> chains, notidentified in the complex, in both fibrinogen and protofibrils. The analysis of the results reveals that infibrinogen the fpA-containing portions are in a more favorable position to bind in the active site cleft ofbound thrombin. Surface plasmon resonance experiments establish that the fpB-containing portions interactwith the fibrin-derived dimeric D-D fragment, suggesting that in protofibrils they bind to the newly formedDD regions bringing fpB into the vicinity of bound thrombin. These findings provide a coherent rationalefor the preferential removal of fpA from fibrinogen at the first stage of fibrin assembly and the acceleratedcleavage of fpB from protofibrils and/or fibrils at the second stage.