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The role of leucine and isoleucine in tuning the hydropathy of class A <scp>GPCRs</scp>


Baumann, Christian; Zerbe, Oliver (2024). The role of leucine and isoleucine in tuning the hydropathy of class A <scp>GPCRs</scp>. Proteins, 92(1):15-23.

Abstract

Leucine and Isoleucine are two amino acids that differ only by the positioning of one methyl group. This small difference can have 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 the 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. We found that Leu side chains are generally more exposed at the protein surface than Ile side chains. We explored whether this difference might be attributed to different functions of the two amino acids and tested if Leu tunes the hydrophobicity of the transmembrane domain based on the Wimley‐White whole‐residue hydrophobicity scales. Leu content decreases the variation in hydropathy between receptors and correlates with the non‐Leu receptor hydropathy. 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 the hydropathy of transmembrane domains of class A GPCRs is tuned by Leu (and to some lesser degree by Lys and Val) to facilitate correct insertion into membranes and/or to stably anchor the receptors within membranes.

Abstract

Leucine and Isoleucine are two amino acids that differ only by the positioning of one methyl group. This small difference can have 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 the 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. We found that Leu side chains are generally more exposed at the protein surface than Ile side chains. We explored whether this difference might be attributed to different functions of the two amino acids and tested if Leu tunes the hydrophobicity of the transmembrane domain based on the Wimley‐White whole‐residue hydrophobicity scales. Leu content decreases the variation in hydropathy between receptors and correlates with the non‐Leu receptor hydropathy. 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 the hydropathy of transmembrane domains of class A GPCRs is tuned by Leu (and to some lesser degree by Lys and Val) to facilitate correct insertion into membranes and/or to stably anchor the receptors within membranes.

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Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Uncontrolled Keywords:Molecular Biology, Biochemistry, Structural Biology
Language:English
Date:1 January 2024
Deposited On:26 Oct 2023 13:38
Last Modified:29 Jun 2024 01:39
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:0887-3585
OA Status:Green
Publisher DOI:https://doi.org/10.1002/prot.26559
PubMed ID:37497770
Project Information:
  • : FunderSNSF
  • : Grant ID159453
  • : Project TitleTowards the solution structure of an entire thermostabilized GPCR
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)