A redox switch in angiotensinogen modulates angiotensin release.
Nature
; 468(7320): 108-11, 2010 Nov 04.
Article
in En
| MEDLINE
| ID: mdl-20927107
ABSTRACT
Blood pressure is critically controlled by angiotensins, 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 inhibitors. Although angiotensinogen has long been regarded as a passive substrate, the crystal structures solved here to 2.1 Å 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 Å 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 4060 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Angiotensins
/
Protein Processing, Post-Translational
/
Angiotensinogen
Limits:
Female
/
Humans
/
Pregnancy
Language:
En
Journal:
Nature
Year:
2010
Type:
Article
Affiliation country:
United kingdom