2025-03-06 バッファロー大学 (UB)
<関連情報>
- https://www.buffalo.edu/news/releases/2025/03/UB-protein-research-pain-therapies.html
- https://www.pnas.org/doi/10.1073/pnas.2406318121
熱受容体の強い温度依存性はタンパク質ダイナミクスに起因する Protein dynamics underlies strong temperature dependence of heat receptors
Andrew Njagi Mugo, Ryan Chou, and Feng Qin
Proceedings of the National Academy of Sciences Published:December 30, 2024
DOI:https://doi.org/10.1073/pnas.2406318121
Significance
Decoding receptor mechanisms requires understanding receptor activation at molecular levels. Whereas structural studies can unravel critical residues participating in activation, functional measurements are ultimately needed to pinpoint their mechanistic roles. Temperature receptors are gateways to thermosensation and pain. Despite intensive studies, how they detect temperature remains elusive. Here, by directly measuring heat flow in the most temperature-sensitive, high-threshold noxious heat receptor TRPV2, we show that channel activation is accompanied with a heat uptake sufficient to induce protein unfolding. We present molecular evidence that heat activation and unfolding are coupled and propose a new mechanism based on concerted activation of different parts of channels to drive up temperature sensitivity. Our findings provide a mechanistic framework for understanding thermal biological processes.
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 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 pieces of evidence 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 multitransition 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.
