Allosterism and Structure in Thermally Activated Transient Receptor Potential Channels

Abstract

The molecular sensors that mediate temperature changes in living organisms are a large family of proteins known as thermosensitive transient receptor potential (TRP) ion channels. These membrane proteins are polymodal receptors that can be activated by cold or hot temperatures, depending on the channel subtype, voltage, and ligands. The stimuli sensors are allosterically coupled to a pore domain, increasing the probability of finding the channel in its ion conductive conformation. In this review we first discuss the allosteric coupling between the temperature and voltage sensor modules and the pore domain, and then discuss the thermodynamic foundations of thermo-TRP channel activation. We provide a structural overview of the molecular determinants of temperature sensing. We also posit an anisotropic thermal diffusion model that may explain the large temperature sensitivity of TRP channels. Additionally, we examine the effect of several ligands on TRP channel function and the evidence regarding their mechanisms of action.

Side chain flexibility and coupling between the S4‐S5 linker and the TRP domain in thermo‐sensitive TRP channels: Insights from protein modeling

“…As TRPV5 and TRPV6 are unique members of the TRP superfamily and closely phylogenetically related, we must mention that the TRPV5 model (based on the relatively distant TRPV2 structure) should be interpreted with this information in mind. Even so, taken all these observations together, our results agree with the general notion of a correlation between a high intrinsic/segmental flexibility in the S6‐TRP box linker as a key structural and a functional determinant that is essential for the allosteric coupling of diverse stimuli in these proteins …”

“…Finally, taking into account that different allosteric models describe the gating of thermo‐sensitive TRP channels, and considering that in all of the cases the corresponding region to the TRP domain at the C‐end of the inner gate plays a central role along with the S4‐S5L during the activation of the channels, our attention was turned to the putative interactions of S4‐S5L with the highly conserved Trp residue present in the TRP box. The results in Figure show that several potential interactions can be established between the Trp residue and the S4‐S5L.…”

“…and Table ); in contrast, the corresponding profiles for TRPV1 and TRPV2 are the most rigid. TRPM8 channels are activated by cold (∼28ºC), whereas TRPV1 and TRPV2 are activated by heat (∼43ºC and ∼52ºC respectively) . Thus, it is tempting to hypothesize a direct relationship between a high flexibility S4‐S5L profile with activation by cooling as well as a restricted flexibility (i.e., an enhanced rigidity) in heat activated TRP channels (see Scheme).…”

Single-residue molecular switch for high-temperature dependence of vanilloid receptor TRPV3

“…Thus, a straightforward interpretation of the large change in the slope sensitivity of TRPV3 is that the process of temperature sensing by the channel becomes altered during activation. For more complex gating mechanisms such as an allosteric paradigm (16), where the stimulus sensor domain is allosterically coupled to the gate, the slope of the gating curve may depend on both stimulus sensor properties and strength of allosteric coupling. However, as illustrated by simulations in Supporting Information, a change in the coupling strength in this case predicted opposite effects on activation threshold and slope sensitivity.…”

Memory of Periodic Thermal Stimulation in an Immune Complex

“…Similar to other C‐terminal regions of Plasmodia MSP1, PvMSP1 19 consists of two successive EGF‐like domains, each EGF‐like domain containing a segment of random coil followed by four antiparallel β‐strands . The presence of these disordered segments affords the augmented protein sensitivity to thermal changes, manifested by increased absorption of the thermal energy from the solvent, transferred to the highly thermally‐conductive β‐sheets . As the temperature is cycled between the two values prior to measurements, either protein exhibits sensitization to temperature, an increase in the protein response to external stimulus, as measured elsewhere for temperature‐activated TRP channels .…”