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Structural basis for the specificity of renin-mediated angiotensinogen cleavage

DOI: 10.1074/jbc.RA118.006608 DOI Help

Authors: Yahui Yan (University of Cambridge) , Aiwu Zhou (Shanghai Jiaotong University School of Medicine) , Robin W. Carrell (University of Cambridge) , Randy J. Read (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Biological Chemistry

State: Published (Approved)
Published: December 2018
Diamond Proposal Number(s): 8547

Abstract: 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.

Journal Keywords: angiotensinogen; serpin; aspartic protease; proteolysis; site-directed mutagenesis; kinetics; renin angiotensin system; hypertension; conformational change; crystal structure

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography