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A redox switch in angiotensinogen modulates angiotensin release

Nature volume 468, pages 108–111 (2010)Cite this article

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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.

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Figure 1: Angiotensinogen and its complex with renin.
Figure 2: Reduced angiotensinogen in plasma.
Figure 3: Kinetics and nitrosylation.
Figure 4: Reduced and oxidized plasma angiotensinogen in pregnancy.

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Primary accessions

Protein Data Bank

Data deposits

Ethical approval was obtained for the use of all patient and control plasmas. Atomic coordinates and structure factors for the reported crystal structures have been deposited with the Protein Data Bank under accession codes 2WXX, 2WXY, 2WXZ, 2WXW, 2WY0, 2WY1 and 2X0B.

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Acknowledgements

This study was funded by the British Heart Foundation, the Wellcome Trust, the Isaac Newton Trust of the University of Cambridge and the UK Medical Research Council, with the support of the Daresbury SRS and Diamond Light Source. We acknowledge the assistance of G. Bunkóczi in data processing, H. Hong for the HPLC measurements of angiotensin, and T. Prime for analysing S-nitrosothiols.

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Authors and Affiliations

  1. Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge, CB2 0XY, UK

    Aiwu Zhou, Zhenquan Wei, Yahui Yan, Peter L. D. Stanley & Randy J. Read

  2. Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge, CB2 0XY, UK

    Robin W. Carrell & Penelope E. Stein

  3. MRC Mitochondrial Biology Unit, Hills Road, Cambridge, CB2 0XY, UK

    Michael P. Murphy

  4. Department of Obstetrics and Gynaecology, University of Nottingham, City Hospital, Nottingham, NG5 1PB, UK

    Fiona Broughton Pipkin

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Contributions

This paper is a culmination of a 20-year study initiated by R.W.C. with P.E.S.; R.W.C. guided the work throughout and wrote the paper with input from A.Z. and R.J.R.; A.Z. designed, performed and analysed all the work reported here, with Z.W., Y.Y. and, for redox studies, with M.P.M.; P.E.S. with P.L.D.S. carried out preceding studies, and F.B.P. provided samples and advice for the pre-eclamptic studies. R.J.R. advised on all aspects of this study and solved the structures. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Aiwu Zhou or Robin W. Carrell.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Methods and additional references, Supplementary Table 1, Supplementary Figures 1-6 with legends and a legend for Supplementary Movie 1. (PDF 1259 kb)

Supplementary Movie 1

The movie file shows the conformational changes that occur when human angiotensinogen binds to human rennin – see Supplementary Information file for full legend. (MOV 7077 kb)

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Zhou, A., Carrell, R., Murphy, M. et al. A redox switch in angiotensinogen modulates angiotensin release. Nature 468, 108–111 (2010). https://doi.org/10.1038/nature09505

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