Role of the Cys18-Cys274 disulfide bond and of the third extracellular loop in the constitutive activation and internalization of angiotensin II type 1 receptor

Regulatory Peptides
Silvana A A CorrêaSuma I Shimuta

Abstract

An insertion of residues in the third extracellular loop and a disulfide bond linking this loop to the N-terminal domain were identified in a structural model of a G-protein coupled receptor specific to angiotensin II (AT1 receptor), built in homology to the seven-transmembrane-helix bundle of rhodopsin. Both the insertion and the disulfide bond were located close to an extracellular locus, flanked by the second extracellular loop (EC-2), the third extracellular loop (EC-3) and the N-terminal domain of the receptor; they contained residues identified by mutagenesis studies to bind the angiotensin II N-terminal segment (residues D1 and R2). It was postulated that the insertion and the disulfide bond, also found in other receptors such as those for bradykinin, endothelin, purine and other ligands, might play a role in regulating the function of the AT1 receptor. This possibility was investigated by assaying AT1 forms devoid of the insertion and with mutations to Ser on both positions of Cys residues forming the disulfide bond. Binding and activation experiments showed that abolition of this bond led to constitutive activation, decay of agonist binding and receptor activation levels. Furthermore, the receptors thus mutated were tr...Continue Reading

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Citations

Oct 26, 2012·Amino Acids·Douglas D LopesClovis R Nakaie
Oct 7, 2009·Biological Chemistry·Alexandre J BarrosClovis R Nakaie
Aug 17, 2010·Biological Chemistry·Renan Paulo MartinSuma Imura Shimuta
Aug 5, 2009·Regulatory Peptides·Renan P MartinSuma I Shimuta
Dec 9, 2008·Molecular and Cellular Endocrinology·Christophe Petrel, Eric Clauser
Aug 26, 2011·British Journal of Pharmacology·M WheatleyJ Barwell
Sep 15, 2012·Biochemical Pharmacology·Ching-I Anderson Wang, Richard J Lewis
Oct 21, 2016·Biochimica Et Biophysica Acta·Prashant KumarGopala Krishna Aradhyam
Apr 13, 2007·Physiological Reviews·Laerte OliveiraAntonio C M Paiva
Nov 28, 2012·The Journal of Biological Chemistry·Lotten RagnarssonRichard J Lewis
Nov 2, 2014·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Romain GerbierXavier Iturrioz
Nov 20, 2015·Biological Chemistry·Rafael Filippelli-SilvaSuma I Shimuta
Sep 24, 2013·Journal of Chemical Information and Modeling·Minos-Timotheos MatsoukasPanagiotis Zoumpoulakis

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