Temperature sensitive contact modes allosterically gate TRPV3.
Temperature sensitive contact modes allosterically gate TRPV3.
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DOI：
10.1371/journal.pcbi.1011545
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发表时间：
2023-10
影响因子：
4.3
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中科院分区：
文献类型：
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TRPV离子通道是设计用于响应不同温度阈值的复杂分子传感器。最近在cryo-EM结构的激增提供了许多见解的结构重排伴随着他们的开放和关闭，然而，TRPV通道建立精确和强大的温度传感的分子机制仍然难以捉摸。在这项工作中，我们采用分子模拟，多系综接触分析，图论和机器学习技术来揭示TRPV 3中驱动变构的温度敏感的残基-残基相互作用。我们发现，表现出类似的温度依赖性的接触频率分布群集在特定区域的通道的残基组。优势模式聚集在锚蛋白重复结构域上，并显示线性熔解趋势，而其他模式则显示非线性趋势。这些模式描述的残留物水平的温度响应模式，通道的功能动态的基础。通过网络分析，我们发现通道的群落结构随着温度的变化而变化。并且高中心性接触的网络将原聚体的远距离区域连接到栅极，作为温度敏感接触模式的手段来变构地调节通道门控。使用随机森林模型，我们表明，特定的温度敏感模式的接触状态确实是预测的沟道门的状态。支持这些模式和网络的物理有效性是几个残基与我们的分析，在文献中报道的功能关键。我们的研究结果提供了高分辨率的洞察热TRP通道功能，并证明了温度敏感的接触分析的实用性。快速而准确的温度感觉对于生物体的生存和体内平衡至关重要。在后生动物中，TRP离子通道家族的成员介导神经热敏。尽管Cryo-EM提供了这些通道的丰富结构细节，但TRP通道的部分传感温度和通道门控的机械细节仍然是一个悬而未决的问题。在这里，我们使用一种新的计算方法来解剖残留水平的温度反应的有害温度报告TRPV 3，并提供一个高分辨率的模型TRPV 3功能，占众多的实验观察。
TRPV Ion channels are sophisticated molecular sensors designed to respond to distinct temperature thresholds. The recent surge in cryo-EM structures has provided numerous insights into the structural rearrangements accompanying their opening and closing; however, the molecular mechanisms by which TRPV channels establish precise and robust temperature sensing remain elusive. In this work we employ molecular simulations, multi-ensemble contact analysis, graph theory, and machine learning techniques to reveal the temperature-sensitive residue-residue interactions driving allostery in TRPV3. We find that groups of residues exhibiting similar temperature-dependent contact frequency profiles cluster at specific regions of the channel. The dominant mode clusters on the ankyrin repeat domain and displays a linear melting trend while others display non-linear trends. These modes describe the residue-level temperature response patterns that underlie the channel’s functional dynamics. With network analysis, we find that the community structure of the channel changes with temperature. And that a network of high centrality contacts connects distant regions of the protomer to the gate, serving as a means for the temperature-sensitive contact modes to allosterically regulate channel gating. Using a random forest model, we show that the contact states of specific temperature-sensitive modes are indeed predictive of the channel gate’s state. Supporting the physical validity of these modes and networks are several residues identified with our analyses that are reported in literature to be functionally critical. Our results offer high resolution insight into thermo-TRP channel function and demonstrate the utility of temperature-sensitive contact analysis. Rapid and accurate temperature sensation is critical for organismal survival and homeostasis. In metazoans, members of the TRP ion channel family mediate neurological thermo-sensing. Despite abundant structural details on these channels provided by Cryo-EM, parts of the TRP channel that sense temperature and mechanistic details of channel gating remains an open question. Here we use a novel computational approach for dissecting the residue-level temperature responses of a noxious temperature reporter TRPV3 and offer a high-resolution model for TRPV3 function that accounts for numerous experimental observations.