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A redox switch in angiotensinogen modulates angiotensin release

DOI: 10.1038/nature09505 DOI Help
PMID: 20927107 PMID Help

Authors: Aiwu Zhou (Department of Haematology, University of Cambridge) , Robin Carrell (Cambridge Institute for Medical Research, University of Cambridge) , Michael Murphy (MRC Mitochondrial Biology Unit) , Zhenquan Wei (Department of Haematology, University of Cambridge) , Yahui Yan (Department of Haematology, University of Cambridge) , Peter Stanley (Institute for Medical Research, University of Cambridge) , Penelope Stein (Institute for Medical Research, University of Cambridge) , Fiona Broughton Pipkin (University of Nottingham) , Randy Read (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature

State: Published (Approved)
Published: October 2010

Open Access Open Access

Abstract: 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 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.

Journal Keywords: Angiotensinogen; Angiotensins; Blood; Crystallography; X-Ray; Disulfides; Female; Humans; Kinetics; Models; Molecular; Oxidation-Reduction; Oxidative; Pre-Eclampsia; Pregnancy; Protein; Post-Translational; Renin

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography