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

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 . 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 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.