Intra-Molecular Connectivity in Sensory Receptors of the TRP Family

Abstract

Membrane voltage, ligand binding, mechanical force and temperature can all induce conformational changes that open ion channel pores. A key question in understanding ion channel function is how the protein domains involved in sensing stimuli communicate with the pore to modulate the state of ion channel's gate. Transient Receptor Potential (TRP) proteins are a large and diverse family of ion channels. Although great advances have been made regarding the activation and modulation of TRP channel activity, detailed molecular mechanisms governing TRP channel gating are still needed. Temperature-activated TRP channels are tightly associated with the detection and integration of sensory input from multiple sensory modalities, emerging as a model to study the inner-workings of polymodal activation. In this context, the intracellular helix dubbed TRP domain (TD) has been suggested as an integrator of input stimuli in TRP channels, however, the mechanics of such integration is currently unknown. Here we show an extensive bioinformatic analysis to fish for bona fide TRP channels from unicellular eukaryotes and compare their primary sequence with orthologs from higher organisms. Evolutionary coupled analysis highlights important interactions connecting the TD with other portions of the channel. Finally, our predictions in combination with genetically encoded non-natural amino acids allow us to trap the open conformation of TRPV1 channels. We propose a mechanistic model for TRP domain-associated integration of the input signals.