Data from: Identification and classification of ion-channels across the tree of life: Insights into understudied CALHM channels

The ion channel (IC) genes encoded in the human genome play fundamental
roles in cellular functions and disease and are one of the largest classes
of druggable proteins. However, limited knowledge of the diverse molecular
and cellular functions carried out by ICs presents a major bottleneck in
developing selective chemical probes for modulating their functions in
disease states. The wealth of sequence data available on ICs from diverse
organisms provides a valuable source of untapped information for
illuminating the unique modes of channel regulation and functional
specialization. However, the extensive diversification of IC sequences and
the lack of a unified resource present a challenge in effectively using
existing data for IC research. Here, we perform integrative mining of
available sequence, structure, and functional data on 419 human ICs across
disparate sources, including extensive literature mining by leveraging
advances in large language models to annotate and curate the full
complement of the “channelome”. We employ a well-established orthology
inference approach to identify and extend the IC orthologs across diverse
organisms to above 48,000. We show that the depth of conservation and
taxonomic representation of IC sequences can further be translated to
functional similarities by clustering them into functionally relevant
groups, which can be used for downstream functional prediction on
understudied members. We demonstrate this by delineating co-conserved
patterns characteristic of the understudied family of the Calcium
Homeostasis Modulator (CALHM) family of ICs. Through mutational analysis
of co-conserved residues altered in human diseases and
electrophysiological studies, we show that evolutionary-constrained
residues significantly alter gating functions. Thus, by providing new
tools and resources for performing large comparative analyses on ICs, this
study addresses the unique needs of the IC community and provides the
groundwork for accelerating the functional characterization of dark
channels for therapeutic intervention.