| Structural highlights
Disease
ANGT_HUMAN Genetic variations in AGT are a cause of susceptibility to essential hypertension (EHT) [MIM:145500. Essential hypertension is a condition in which blood pressure is consistently higher than normal with no identifiable cause. Defects in AGT are a cause of renal tubular dysgenesis (RTD) [MIM:267430. RTD is an autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype).[1]
Function
ANGT_HUMAN Essential component of the renin-angiotensin system (RAS), a potent regulator of blood pressure, body fluid and electrolyte homeostasis.[2] [3] [4] Angiotensin-2: acts directly on vascular smooth muscle as a potent vasoconstrictor, affects cardiac contractility and heart rate through its action on the sympathetic nervous system, and alters renal sodium and water absorption through its ability to stimulate the zona glomerulosa cells of the adrenal cortex to synthesize and secrete aldosterone.[5] [6] [7] Angiotensin-3: stimulates aldosterone release.[8] [9] [10] Angiotensin 1-7: is a ligand for the G-protein coupled receptor MAS1 (By similarity). Has vasodilator and antidiuretic effects (By similarity). Has an antithrombotic effect that involves MAS1-mediated release of nitric oxide from platelets (By similarity).[11] [12] [13]
Publication Abstract from PubMed
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 A resolution), its encounter complex with renin (2.55 A), AGT cleaved in its reactive center loop (RCL; 2.97 A) and spent AGT from which the N-terminal angiotensin peptide was removed (2.63 A). 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.
Structural basis for the specificity of renin-mediated angiotensinogen cleavage.,Yan Y, Zhou A, Carrell RW, Read RJ J Biol Chem. 2018 Dec 18. pii: RA118.006608. doi: 10.1074/jbc.RA118.006608. PMID:30563843[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Gribouval O, Gonzales M, Neuhaus T, Aziza J, Bieth E, Laurent N, Bouton JM, Feuillet F, Makni S, Ben Amar H, Laube G, Delezoide AL, Bouvier R, Dijoud F, Ollagnon-Roman E, Roume J, Joubert M, Antignac C, Gubler MC. Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. Nat Genet. 2005 Sep;37(9):964-8. Epub 2005 Aug 14. PMID:16116425 doi:ng1623
- ↑ Goodfriend TL, Peach MJ. Angiotensin III: (DES-Aspartic Acid-1)-Angiotensin II. Evidence and speculation for its role as an important agonist in the renin - angiotensin system. Circ Res. 1975 Jun;36(6 Suppl 1):38-48. PMID:1132082
- ↑ Weir MR, Dzau VJ. The renin-angiotensin-aldosterone system: a specific target for hypertension management. Am J Hypertens. 1999 Dec;12(12 Pt 3):205S-213S. PMID:10619573
- ↑ Jankowski V, Vanholder R, van der Giet M, Tolle M, Karadogan S, Gobom J, Furkert J, Oksche A, Krause E, Tran TN, Tepel M, Schuchardt M, Schluter H, Wiedon A, Beyermann M, Bader M, Todiras M, Zidek W, Jankowski J. Mass-spectrometric identification of a novel angiotensin peptide in human plasma. Arterioscler Thromb Vasc Biol. 2007 Feb;27(2):297-302. Epub 2006 Nov 30. PMID:17138938 doi:10.1161/01.ATV.0000253889.09765.5f
- ↑ Goodfriend TL, Peach MJ. Angiotensin III: (DES-Aspartic Acid-1)-Angiotensin II. Evidence and speculation for its role as an important agonist in the renin - angiotensin system. Circ Res. 1975 Jun;36(6 Suppl 1):38-48. PMID:1132082
- ↑ Weir MR, Dzau VJ. The renin-angiotensin-aldosterone system: a specific target for hypertension management. Am J Hypertens. 1999 Dec;12(12 Pt 3):205S-213S. PMID:10619573
- ↑ Jankowski V, Vanholder R, van der Giet M, Tolle M, Karadogan S, Gobom J, Furkert J, Oksche A, Krause E, Tran TN, Tepel M, Schuchardt M, Schluter H, Wiedon A, Beyermann M, Bader M, Todiras M, Zidek W, Jankowski J. Mass-spectrometric identification of a novel angiotensin peptide in human plasma. Arterioscler Thromb Vasc Biol. 2007 Feb;27(2):297-302. Epub 2006 Nov 30. PMID:17138938 doi:10.1161/01.ATV.0000253889.09765.5f
- ↑ Goodfriend TL, Peach MJ. Angiotensin III: (DES-Aspartic Acid-1)-Angiotensin II. Evidence and speculation for its role as an important agonist in the renin - angiotensin system. Circ Res. 1975 Jun;36(6 Suppl 1):38-48. PMID:1132082
- ↑ Weir MR, Dzau VJ. The renin-angiotensin-aldosterone system: a specific target for hypertension management. Am J Hypertens. 1999 Dec;12(12 Pt 3):205S-213S. PMID:10619573
- ↑ Jankowski V, Vanholder R, van der Giet M, Tolle M, Karadogan S, Gobom J, Furkert J, Oksche A, Krause E, Tran TN, Tepel M, Schuchardt M, Schluter H, Wiedon A, Beyermann M, Bader M, Todiras M, Zidek W, Jankowski J. Mass-spectrometric identification of a novel angiotensin peptide in human plasma. Arterioscler Thromb Vasc Biol. 2007 Feb;27(2):297-302. Epub 2006 Nov 30. PMID:17138938 doi:10.1161/01.ATV.0000253889.09765.5f
- ↑ Goodfriend TL, Peach MJ. Angiotensin III: (DES-Aspartic Acid-1)-Angiotensin II. Evidence and speculation for its role as an important agonist in the renin - angiotensin system. Circ Res. 1975 Jun;36(6 Suppl 1):38-48. PMID:1132082
- ↑ Weir MR, Dzau VJ. The renin-angiotensin-aldosterone system: a specific target for hypertension management. Am J Hypertens. 1999 Dec;12(12 Pt 3):205S-213S. PMID:10619573
- ↑ Jankowski V, Vanholder R, van der Giet M, Tolle M, Karadogan S, Gobom J, Furkert J, Oksche A, Krause E, Tran TN, Tepel M, Schuchardt M, Schluter H, Wiedon A, Beyermann M, Bader M, Todiras M, Zidek W, Jankowski J. Mass-spectrometric identification of a novel angiotensin peptide in human plasma. Arterioscler Thromb Vasc Biol. 2007 Feb;27(2):297-302. Epub 2006 Nov 30. PMID:17138938 doi:10.1161/01.ATV.0000253889.09765.5f
- ↑ Yan Y, Zhou A, Carrell RW, Read RJ. Structural basis for the specificity of renin-mediated angiotensinogen cleavage. J Biol Chem. 2018 Dec 18. pii: RA118.006608. doi: 10.1074/jbc.RA118.006608. PMID:30563843 doi:http://dx.doi.org/10.1074/jbc.RA118.006608
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