Abstract
Ion channels are generally allosteric proteins, involving specialized stimulus sensor domains conformationally linked to the gate to drive channel opening. Temperature receptors are a group of ion channels from the transient receptor potential (TRP) family. They exhibit an unprecedentedly strong temperature dependence and are responsible for temperature sensing in mammals. Despite intensive studies, however, the nature of the temperature sensor domain in these channels remains elusive. By direct calorimetry of TRPV1 proteins, we have recently provided a proof of principle that temperature sensing by ion channels may diverge from the conventional allosterity theory; rather it is intimately linked to inherent thermal instability of channel proteins. Here we tackle the generality of the hypothesis and provide key molecular evidences on the coupling of thermal transitions in the channels. We show that while wild-type channels possess a single concerted thermal transition peak, the chimera, in which strong temperature dependence becomes disrupted, results in multi-transition peaks, and the activation enthalpies are accordingly reduced. The data show that the coupling with protein unfolding drives up the energy barrier of activation, leading to a strong temperature dependence of opening. Furthermore, we pinpoint the proximal N-terminus of the channels as a linchpin in coalescing different parts of the channels into concerted activation. Thus, we suggest that coupled interaction networks in proteins underlie the strong temperature dependence of temperature receptors.