AUTHOR=Shu Zimei , Wan Jiahui , Read Randy J. , Carrell Robin W. , Zhou Aiwu 

TITLE=Angiotensinogen and the Modulation of Blood Pressure

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 8 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.645123

DOI=10.3389/fcvm.2021.645123

ISSN=2297-055X

ABSTRACT=The angiotensin peptides that control blood pressure are released from the non-inhibitory plasma serpin, angiotensinogen on cleavage of its extended N-terminal tail by the specific aspartyl-protease, renin. Angiotensinogen had previously been assumed to be a passive substrate but recent structural studies reveal a conformational mechanism that is critical to the release of the angiotensin peptides and hence to the control of blood pressure. Interaction with renin triggers a profound shift of the amino-terminal tail of angiotensinogen, exposing its buried cleavage centre and establishing the renin-binding site. Modulation occurs at several levels. The tail of angiotensinogen is restrained by a labile disulphide bond (Cys18-Cys138), with changes in it's redox status affecting angiotensin release, as demonstrably so in the hypertensive complication of pregnancy, pre-eclampsia. The shift of the tail also enhances the binding of renin through a tail-in-mouth allosteric mechanism. The N-terminus is now seen to insert into a pocket equivalent to the hormone-binding site on other serpins, with helix H of angiotensinogen unwinding to form key interactions with renin in the complementary binding interface. The findings explain the precise species specificity of the interaction with renin and with variant carbohydrate linkages. Overall, these studies provide new insights into the physiological regulation of angiotensin release, with an ability to respond to local tissue and temperature changes, and with the opening of new strategies for the development of novel agents for the treatment of hypertension.