Data from: 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,
DUF3537, PHTF and GrlHz) are homologous or convergent, leaving their
evolutionary history unresolved. Our pipeline identified thousands of new
7TMICs in archaea, bacteria and unicellular eukaryotes. Using graph-based
analyses and protein language models to extract family-wide signatures, we
demonstrate that 7TMICs have structure and sequence similarity, supporting
homology. Through sequence and structure-based phylogenetics, we classify
eukaryotic 7TMICs into two families (Class-A and Class-B), which are the
result of a gene duplication predating the split(s) leading to Amorphea
(animals, fungi and allies) and Diaphoretickes (plants and allies). Our
work reveals 7TMICs as a cryptic superfamily with origins close to the
evolution of cellular life. More generally, this study serves as a
methodological proof of principle for the identification of extremely
distant protein homologs.