title: Comparative sequence analysis suggests a conserved gating mechanism for TRP channels.
abstract: The transient receptor potential (TRP) channel superfamily plays a central role in transducing diverse sensory stimuli in eukaryotes. Although dissimilar in sequence and domain organization, all known TRP channels act as polymodal cellular sensors and form tetrameric assemblies similar to those of their distant relatives, the voltage-gated potassium (Kv) channels. Here, we investigated the related questions of whether the allosteric mechanism underlying polymodal gating is common to all TRP channels, and how this mechanism differs from that underpinning Kv channel voltage sensitivity. To provide insight into these questions, we performed comparative sequence analysis on large, comprehensive ensembles of TRP and Kv channel sequences, contextualizing the patterns of conservation and correlation observed in the TRP channel sequences in light of the well-studied Kv channels. We report sequence features that are specific to TRP channels and, based on insight from recent TRPV1 structures, we suggest a model of TRP channel gating that differs substantially from the one mediating voltage sensitivity in Kv channels. The common mechanism underlying polymodal gating involves the displacement of a defect in the H-bond network of S6 that changes the orientation of the pore-lining residues at the hydrophobic gate.
authors.affiliation: Institute for Computational Molecular Science, Temple University, Philadelphia, PA 19122.
authors.forename: Eugene
authors.initials: E
authors.lastname: Palovcak
authors.affiliation: Institute for Computational Molecular Science, Temple University, Philadelphia, PA 19122.
authors.forename: Lucie
authors.initials: L
authors.lastname: Delemotte
authors.affiliation: Institute for Computational Molecular Science, Temple University, Philadelphia, PA 19122.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Klein
authors.affiliation: Institute for Computational Molecular Science, Temple University, Philadelphia, PA 19122 vincenzo.carnevale@temple.edu.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Carnevale
mesh_terms: D000494:Allosteric Regulation / Q000235:genetics; D000595:Amino Acid Sequence; D017124:Conserved Sequence / Q000235:genetics*; D015640:Ion Channel Gating / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015221:Potassium Channels / Q000235:genetics; D017421:Sequence Analysis; D050051:Transient Receptor Potential Channels / Q000235:genetics*
chemical_list: D015221:Potassium Channels; D050051:Transient Receptor Potential Channels