Structural screens identify candidate human homologs of insect chemoreceptors and cryptic Drosophila gustatory receptor-like proteins
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eLife assessment
Overall, this manuscript provides fundamental advances to our understanding of the ancestry of insect gustatory and olfactory receptors, by identifying new members of these two related ion channel families in distant species. The approaches to compare protein structure are exceptional and use cutting-edge techniques, going beyond the commonly used approaches. The authors suggest that the family of odorant and gustatory receptors have a common origin and share structural homology in very distant organisms, although the possibility of convergent evolution still exists. This work will serve as a reference for scientists working on insect olfaction and for those working on molecular evolution.
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Abstract
Insect odorant receptors and gustatory receptors define a superfamily of seven transmembrane domain ion channels (referred to here as 7TMICs), with homologs identified across Animalia except Chordata. Previously, we used sequence-based screening methods to reveal conservation of this family in unicellular eukaryotes and plants (DUF3537 proteins) (Benton et al., 2020). Here, we combine three-dimensional structure-based screening, ab initio protein folding predictions, phylogenetics, and expression analyses to characterize additional candidate homologs with tertiary but little or no primary structural similarity to known 7TMICs, including proteins in disease-causing Trypanosoma . Unexpectedly, we identify structural similarity between 7TMICs and PHTF proteins, a deeply conserved family of unknown function, whose human orthologs display enriched expression in testis, cerebellum, and muscle. We also discover divergent groups of 7TMICs in insects, which we term the gustatory receptor-like (Grl) proteins. Several Drosophila melanogaster Grl s display selective expression in subsets of taste neurons, suggesting that they are previously unrecognized insect chemoreceptors. Although we cannot exclude the possibility of remarkable structural convergence, our findings support the origin of 7TMICs in a eukaryotic common ancestor, counter previous assumptions of complete loss of 7TMICs in Chordata, and highlight the extreme evolvability of this protein fold, which likely underlies its functional diversification in different cellular contexts.
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eLife assessment
Overall, this manuscript provides fundamental advances to our understanding of the ancestry of insect gustatory and olfactory receptors, by identifying new members of these two related ion channel families in distant species. The approaches to compare protein structure are exceptional and use cutting-edge techniques, going beyond the commonly used approaches. The authors suggest that the family of odorant and gustatory receptors have a common origin and share structural homology in very distant organisms, although the possibility of convergent evolution still exists. This work will serve as a reference for scientists working on insect olfaction and for those working on molecular evolution.
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Reviewer #1 (Public Review):
Insect chemosensory receptors function as ligand-gated ion channels, while vertebrate and nematode chemoreceptors are G-protein coupled receptors. This difference led to multiple questions. One was whether there are vertebrate homologs of insect chemosensory receptors or receptor-like proteins. This manuscript of Benton and Himmel titled "Structural screens identify candidate human homologs of insect chemoreceptors and cryptic Drosophila gustatory receptor-like proteins" addressed this key question. First, it showed consistent results using the new tool for protein structure prediction, AlphaFold2, and confirmed the previously identified OR, GR, GRL, and DUF proteins in the 7TMIC superfamily as structural homologs of Orco. Then the authors identified human/vertebrate homologs: PHTF, but the function of this …
Reviewer #1 (Public Review):
Insect chemosensory receptors function as ligand-gated ion channels, while vertebrate and nematode chemoreceptors are G-protein coupled receptors. This difference led to multiple questions. One was whether there are vertebrate homologs of insect chemosensory receptors or receptor-like proteins. This manuscript of Benton and Himmel titled "Structural screens identify candidate human homologs of insect chemoreceptors and cryptic Drosophila gustatory receptor-like proteins" addressed this key question. First, it showed consistent results using the new tool for protein structure prediction, AlphaFold2, and confirmed the previously identified OR, GR, GRL, and DUF proteins in the 7TMIC superfamily as structural homologs of Orco. Then the authors identified human/vertebrate homologs: PHTF, but the function of this protein is not clear. Finally, they further expanded drosophilid-specific GRL proteins. It is great to see new members of the 7TMIC superfamily!
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Reviewer #2 (Public Review):
The chemosensory systems of vertebrates and insects share a lot of structural and functional similarities. However, looking deeper into their molecular components reveals that these similarities likely represent remarkable examples of convergent evolution. For instance, receptor molecules that detect odors are unrelated between vertebrates and insects - vertebrates use G-protein coupled receptors while insects use ligand-gated ion channels. The latter was long regarded as specific to insects, but later studies identified putative homologs in other animals, (but not in vertebrates), some unicellular eukaryotes, and plants, raising the possibility that it is an ancient family. Still, the evolution of this protein family is notoriously difficult to analyze due to a high degree of sequence divergence between the …
Reviewer #2 (Public Review):
The chemosensory systems of vertebrates and insects share a lot of structural and functional similarities. However, looking deeper into their molecular components reveals that these similarities likely represent remarkable examples of convergent evolution. For instance, receptor molecules that detect odors are unrelated between vertebrates and insects - vertebrates use G-protein coupled receptors while insects use ligand-gated ion channels. The latter was long regarded as specific to insects, but later studies identified putative homologs in other animals, (but not in vertebrates), some unicellular eukaryotes, and plants, raising the possibility that it is an ancient family. Still, the evolution of this protein family is notoriously difficult to analyze due to a high degree of sequence divergence between the genes despite the shared structural features of the proteins they encode. Here, the authors make use of the recent explosion of high-quality structural predictions produced by AlphaFold to conduct a deep search for previously undiscovered homologs of insect odorant and gustatory receptors.
The study describes two major findings:
1. In contrast to the previous idea that vertebrates lack any homologs of the insect receptors, two proteins in vertebrates turn out to display a similar structure (Fig. 2B).
2. The authors describe a previously uncharacterized family of Drosophila "gustatory receptor-like" proteins with a putative function in chemoreception as suggested by expression data (Fig 3A, G).All analyses are extremely thorough, the logic of the narrative is very clear, and I find all conclusions well supported by data. The authors clearly favor a hypothesis that the family that includes insect odorant and gustatory receptors has a very deep evolutionary origin, and the homologous genes in other animals and non-animals have strongly diverged at the level of the sequence but retained detectable structural homology. However, they also acknowledge the limitations of some of their arguments and they discuss an alternative whereby the observed structural similarity is the result of convergence (which would be equally interesting). Overall, this study represents a major advance in our understanding of protein evolution and opens several avenues of research into the question of how functional demands steer the preservation of structural features of proteins while allowing their amino acid sequences to diverge.
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Reviewer #3 (Public Review):
The Odorant Receptor and Gustatory Receptor families of 7 Transmembrane domain Ion channels were previously believed to have no family members in vertebrates. This paper uses the recent advances in protein folding prediction tools to first validate previous discoveries and confirm their approach with genes of known function. They then search for new family members and discover additional related genes in insects, where both ORs and IRs were previously known to exist. The most striking finding of the paper is that they identify genes related to these protein families in vertebrates, including humans. They propose a model for the evolution of this gene family based on their data.
Overall, the data in this paper is strong, the data presentation is clear and the text is well-written and scholarly. The main …
Reviewer #3 (Public Review):
The Odorant Receptor and Gustatory Receptor families of 7 Transmembrane domain Ion channels were previously believed to have no family members in vertebrates. This paper uses the recent advances in protein folding prediction tools to first validate previous discoveries and confirm their approach with genes of known function. They then search for new family members and discover additional related genes in insects, where both ORs and IRs were previously known to exist. The most striking finding of the paper is that they identify genes related to these protein families in vertebrates, including humans. They propose a model for the evolution of this gene family based on their data.
Overall, the data in this paper is strong, the data presentation is clear and the text is well-written and scholarly. The main weaknesses of the paper are that they have no functional analysis of any of their newly discovered proteins. This paper would benefit from experimental evidence that these are functional ligand-gated ion channels. The authors discuss this limitation at the end of the paper and note the challenges that conducting a functional analysis of these channels would represent. We agree that this could take years and that it is beyond the scope of the current paper, although we eagerly await a follow-up study where those experiments might be done.
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