Remote homolog detection places insect chemoreceptors in a cryptic protein superfamily spanning the tree of life

Many proteins exist in the so-called “twilight zone” of sequence alignment, where low pairwise sequence identity makes it difficult to determine homology and phylogeny. As protein tertiary structure is often more conserved, recent advances in ab initio protein folding have made structure-based identification of putative homologs feasible. However, structural screening and phylogenetics are in their infancy, particularly for twilight zone proteins. We present a pipeline for the identification and characterization of distant homologs, and apply it to 7-transmembrane domain ion channels (7TMICs), a protein group founded by insect Odorant and Gustatory receptors. Previous sequence and limited structure-based searches identified putatively-related proteins, mainly in other animals and plants. However, very few 7TMICs have been identified in non-animal, non-plant taxa. Moreover, these proteins’ remarkable sequence dissimilarity made it uncertain if disparate 7TMIC types (Gr/Or, Grl, GRL, DUF3...