Coevolutionary Signals in Metabotropic Glutamate Receptors Capture Residue Contacts and Long-Range Functional Interactions

Authors

Eunna Huh
Melina A Agosto
Theodore G Wensel
Olivier Lichtarge

Publication Date

4-1-2023

Journal

Journal of Biological Chemistry

DOI

10.1016/j.jbc.2023.103030

PMID

36806686

PMCID

PMC10060750

PubMedCentral® Posted Date

2-17-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Receptors, Metabotropic Glutamate, Binding Sites, Phylogeny, Ligands, Receptors, G-Protein-Coupled, G protein–coupled receptor, G protein, structure–function, protein evolution, coevolutionary signals

Abstract

Upon ligand binding to a G protein-coupled receptor, extracellular signals are transmitted into a cell through sets of residue interactions that translate ligand binding into structural rearrangements. These interactions needed for functions impose evolutionary constraints so that, on occasion, mutations in one position may be compensated by other mutations at functionally coupled positions. To quantify the impact of amino acid substitutions in the context of major evolutionary divergence in the G protein-coupled receptor subfamily of metabotropic glutamate receptors (mGluRs), we combined two phylogenetic-based algorithms, Evolutionary Trace and covariation Evolutionary Trace, to infer potential structure-function couplings and roles in mGluRs. We found a subset of evolutionarily important residues at known functional sites and evidence of coupling among distinct structural clusters in mGluR. In addition, experimental mutagenesis and functional assays confirmed that some highly covariant residues are coupled, revealing their synergy. Collectively, these findings inform a critical step toward understanding the molecular and structural basis of amino acid variation patterns within mGluRs and provide insight for drug development, protein engineering, and analysis of naturally occurring variants.

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