Structural basis for the specificity of renin-mediated angiotensinogen cleavage.

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The renin-angiotensin cascade is a hormone system that regulates blood pressure and fluid balance. Renin-mediated cleavage of the angiotensin I peptide from the N terminus of angiotensinogen (AGT) is the rate-limiting step of this cascade; however, the detailed molecular mechanism underlying this step is unclear. Here, we solved the crystal structures of glycosylated human AGT (2.30 Å resolution), its encounter complex with renin (2.55 Å), AGT cleaved in its reactive center loop (RCL; 2.97 Å), and spent AGT from which the N-terminal angiotensin peptide was removed (2.63 Å). These structures revealed that AGT undergoes profound conformational changes and binds renin through a tail-into-mouth allosteric mechanism that inserts the N terminus into a pocket equivalent to a hormone-binding site on other serpins. These changes fully extended the N-terminal tail, with the scissile bond for angiotensin release docked in renin's active site. Insertion of the N terminus into this pocket accompanied a complete unwinding of helix H of AGT, which, in turn, formed key interactions with renin in the complementary binding interface. Mutagenesis and kinetic analyses confirmed that renin-mediated production of angiotensin I is controlled by interactions of amino acid residues and glycan components outside renin's active-site cleft. Our findings indicate that AGT adapts unique serpin features for hormone delivery and binds renin through concerted movements in the N-terminal tail and in its main body to modulate angiotensin release. These insights provide a structural basis for the development of agents that attenuate angiotensin release by targeting AGT's hormone binding pocket.

angiotensinogen, aspartic protease, conformational change, crystal structure, hypertension, kinetics, proteolysis, renin angiotensin system, serpin, site-directed mutagenesis, Allosteric Regulation, Angiotensin I, Angiotensinogen, Crystallography, X-Ray, Humans, Protein Domains, Renin
Journal Title
J Biol Chem
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Elsevier BV
British Heart Foundation (None)
Wellcome Trust (209407/Z/17/Z)
Wellcome Trust (082961/Z/07/Z)
Wellcome Trust (100140/Z/12/Z)