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A role for transmembrane domains V and VI in ligand binding and maturation of the angiotensin II AT1 receptor

  • Graciela C. Pignatari , Raphael Rozenfeld , Emer S. Ferro , Laerte Oliveira , Antonio C.M. Paiva and Lakshmi A. Devi
Published/Copyright: March 17, 2006
Biological Chemistry
From the journal Volume 387 Issue 3

Abstract

Several studies have proposed that angiotensin II (Ang II) binds to its receptor AT1 through interactions with residues in helices V and VI, suggesting that the distance between these helices is crucial for ligand binding. Based on a 3D model of AT1 in which the C-terminus of Ang II is docked, we identified the hydrophobic residues of TM V and VI pointing towards the external face of the helices, which may play a role in the structure of the binding pocket and in the structural integrity of the receptor. We performed a systematic mutagenesis study of these residues and examined the binding, localization, maturation, and dimerization of the mutated receptors. We found that mutations of hydrophobic residues to alanine in helix V do not alter binding, whereas mutations to glutamate lead to loss of binding without a loss in cell surface expression, suggesting that the external face of helix V may not directly participate in binding, but may rather contribute to the structure of the binding pocket. In contrast, mutations of hydrophobic residues to glutamate in helix VI lead to a loss in cell surface expression, suggesting that the external surface of helix VI plays a structural role and ensures correct folding of the receptor.

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Published Online: 2006-03-17
Published in Print: 2006-03-01

©2006 by Walter de Gruyter Berlin New York

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