A redox switch in angiotensinogen modulates angiotensin release.

TitleA redox switch in angiotensinogen modulates angiotensin release.
Publication TypeJournal Article
Year of Publication2010
AuthorsZhou, A, Carrell, RW, Murphy, MP, Wei, Z, Yan, Y, Stanley, PLD, Stein, PE, Pipkin, FBroughton, Read, RJ
JournalNature
Volume468
Issue7320
Pagination108-11
Date Published2010 Nov 04
ISSN1476-4687
KeywordsAmino Acid Sequence, Angiotensinogen, Angiotensins, Blood Pressure, Crystallography, X-Ray, Disulfides, Female, Humans, Kinetics, Models, Molecular, Molecular Sequence Data, Oxidation-Reduction, Oxidative Stress, Pre-Eclampsia, Pregnancy, Protein Conformation, Protein Processing, Post-Translational, Renin
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 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.

DOI10.1038/nature09505
Alternate JournalNature
Citation Key10.1038/nature09505
PubMed ID20927107
PubMed Central IDPMC3024006
Grant List082961 / / Wellcome Trust / United Kingdom
PG/09/072/27945 / / British Heart Foundation / United Kingdom
PG/08/041/24818 / / British Heart Foundation / United Kingdom
MC_U105663142 / / Medical Research Council / United Kingdom
BS/05/002/18361 / / British Heart Foundation / United Kingdom