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Leucine tunes hydropathy of class A GPCRs
  • Christian Baumann,
  • Oliver Zerbe
Christian Baumann
Universitat Zurich Institut fur Chemie

Corresponding Author:christian.baumann@chem.uzh.ch

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Oliver Zerbe
Universitat Zurich Institut fur Chemie
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Leucine and Isoleucine are two amino acids that differ only by the positioning of one methyl group. This small difference has however important consequences in α-helices, as the β-branching of Ile results in helix destabilization. We set out to investigate whether there are general trends for the occurrences of Leu and Ile residues in structures and sequences of class A GPCRs (G protein-coupled receptors). GPCRs are integral membrane proteins in which α-helices span the plasma membrane seven times and which play a crucial role in signal transmission into the cell. We found that Leu side chains are generally present in less densely packed regions and are more protein-surface exposed than Ile side chains. We explored whether this difference might be attributed to different functions of the two amino acids and tested if Leu adjusts the hydrophobicity of the transmembrane domain based on the Wimley-White whole-residue hydrophobicity scales. In class A GPCRs, Leu decreases the variation in hydropathy between receptors and Leu content correlates positively with hydropathy calculated without Leu. Both measures indicate that hydropathy is tuned by Leu. To test this idea further, we generated protein sequences with random amino acid compositions using a simple numerical model, in which hydropathy was tuned by adjusting the number of Leu residues. The model was able to replicate the observations made with class A GPCR sequences. We speculate that Leu tunes the hydropathy of the transmembrane domain of class A GPCRs to facilitate correct insertion into membranes and/or for stability within them.
17 Mar 2023Submitted to PROTEINS: Structure, Function, and Bioinformatics
17 Mar 2023Assigned to Editor
17 Mar 2023Submission Checks Completed
17 Mar 2023Review(s) Completed, Editorial Evaluation Pending
20 Mar 2023Reviewer(s) Assigned