Structural screens identify candidate human homologs of insect chemoreceptors and cryptic Drosophila gustatory receptor-like proteins

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Abstract

Insect Odorant receptors and Gustatory receptors define a superfamily of seven-transmembrane domain ligand-gated 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 Grls 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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

The following previously published data sets were used

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Article and author information

Author details

Richard Benton

Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland

For correspondence
Richard.Benton@unil.ch

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-4305-8301
Nathaniel J Himmel

Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland

For correspondence
nathanieljohn.himmel@unil.ch

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7876-6960

Funding

H2020 European Research Council (833548)

Richard Benton

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030B-185377)

Richard Benton

Human Frontier Science Program (LT-0003/2022-L)

Nathaniel J Himmel

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.