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

Biol Chem. 2006 Mar;387(3):269-76. doi: 10.1515/BC.2006.036.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / chemistry
  • Alanine / genetics
  • Amino Acid Sequence
  • Angiotensin II / chemistry
  • Angiotensin II / genetics
  • Angiotensin II / metabolism*
  • Cell Membrane / genetics
  • Cell Membrane / metabolism
  • Gene Expression Regulation
  • Glutamic Acid / chemistry
  • Glutamic Acid / genetics
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Ligands
  • Membrane Proteins / chemistry*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Molecular Sequence Data
  • Mutation
  • Protein Binding
  • Protein Structure, Secondary*
  • Protein Structure, Tertiary
  • Receptor, Angiotensin, Type 1 / chemistry
  • Receptor, Angiotensin, Type 1 / genetics
  • Receptor, Angiotensin, Type 1 / metabolism*


  • Ligands
  • Membrane Proteins
  • Receptor, Angiotensin, Type 1
  • Angiotensin II
  • Glutamic Acid
  • Alanine