Nature:血压的一个控制点

2010-11-05 00:00 · ada

一项长达20年的工作,成功识别出了释放血管加压肽“血管紧张素”、从而控制血压的分子相互作用中的启动步骤。“血管紧张素”是一种更大的分子“血管紧张肽原”被名为“肾素”的酶解理而产生的。现在单独的“血管紧张肽原”以及与“肾素”相结合的“血管紧张肽原”的晶体结构都表明,要露出“肾素”解

一项长达20年的工作,成功识别出了释放血管加压肽“血管紧张素”、从而控制血压的分子相互作用中的启动步骤。“血管紧张素”是一种更大的分子“血管紧张肽原”被名为“肾素”的酶解理而产生的。现在单独的“血管紧张肽原”以及与“肾素”相结合的“血管紧张肽原”的晶体结构都表明,要露出“肾素”解理点需要一个大的构形变化。

这个过渡由氧化来调控,有“先兆子痫”(亦称“子痫前期”,与高血压有关)的妇女,该物质更为活跃的氧化形式含量更高。


推荐英文摘要:

Nature doi:10.1038/nature09505

A redox switch in angiotensinogen modulates angiotensin release

Aiwu Zhou,awz20@cam.ac.ukRobin W. Carrell,rwc1000@cam.ac.ukMichael P. Murphy,Zhenquan Wei,Yahui Yan,Peter L. D. Stanley,Penelope E. Stein,Fiona Broughton Pipkin" Randy J. Read

Blood pressure is critically controlled by angiotensins1, which are vasopressor peptides specifically released by the enzyme renin from the tail of angiotensinogen―a non-inhibitory member of the serpin family of protease inhibitors2, 3. Although angiotensinogen has long been regarded as a passive substrate, the crystal structures solved here to 2.1?? resolution show that the angiotensin cleavage site is inaccessibly buried in its amino-terminal tail. The conformational rearrangement that makes this site accessible for proteolysis is revealed in our 4.4?? structure of the complex of human angiotensinogen with renin. The co-ordinated changes involved are seen to be critically linked by a conserved but labile disulphide bridge. Here we show that the reduced unbridged form of angiotensinogen is present in the circulation in a near 40:60 ratio with the oxidized sulphydryl-bridged form, which preferentially interacts with receptor-bound renin. We propose that this redox-responsive transition of angiotensinogen to a form that will more effectively release angiotensin at a cellular level contributes to the modulation of blood pressure. Specifically, we demonstrate the oxidative switch of angiotensinogen to its more active sulphydryl-bridged form in the maternal circulation in pre-eclampsia―the hypertensive crisis of pregnancy that threatens the health and survival of both mother and child.

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