PDF(Pubmed)
Abstract：
The inositol 1,4,5-triphosphate receptor (IP3R) mediates Ca release in many cell types and is pivotal to a wide range of cellular processes. High-resolution cryoelectron microscopy studies have provided new structural details of IP3R type 1 (IP3R1), showing that channel function is determined by the movement of various domains within and between each of its four subunits. Channel properties are regulated by ligands, such as Ca and IP3, which bind at specific sites and control the interactions between these domains. However, it is not known how the various ligand-binding sites on IP3R1 interact to control the opening of the channel. In this study, we present a coarse-grained model of IP3R1 that accounts for the channel architecture and the location of specific Ca- and IP3-binding sites. This computational model accounts for the domain-domain interactions within and between the four subunits that form IP3R1, and it also describes how ligand binding regulates these interactions. Using a kinetic model, we explore how two Ca-binding sites on the cytosolic side of the channel interact with the IP3-binding site to regulate the channel open probability. Our primary finding is that the bell-shaped open probability of IP3R1 provides constraints on the relative strength of these regulatory binding sites. In particular, we argue that a specific Ca-binding site, whose function has not yet been established, is very likely a channel antagonist. Additionally, we apply our model to show that domain-domain interactions between neighboring subunits exert control over channel cooperativity and dictate the nonlinear response of the channel to Ca concentration. This suggests that specific domain-domain interactions play a pivotal role in maintaining the channel\'s stability, and a disruption of these interactions may underlie disease states associated with Ca dysregulation.
摘要：
肌醇1,4,5-三磷酸受体（IP3R）在许多细胞类型中介导Ca的释放，并且对广泛的细胞过程至关重要。高分辨率低温电子显微镜（Cryo-EM）研究提供了IP3R1型（IP3R1）的新结构细节，表明通道功能是由其四个亚基中每个亚基内部和之间的各个域的运动决定的。通道特性受配体调节，例如Ca和IP3,其在特定位点结合并控制这些结构域之间的相互作用。然而,尚不清楚IP3R1上的各种配体结合位点如何相互作用以控制通道的开放。在这项研究中，我们提出了IP3R1的粗粒度模型，该模型解释了通道结构以及特定Ca和IP3结合位点的位置。该计算模型解释了形成IP3R1的四个亚基内部和之间的结构域-结构域相互作用，并且还描述了配体结合如何调节这些相互作用。使用动力学模型，我们探讨了通道胞质侧的两个Ca结合位点如何与IP3结合位点相互作用以调节通道开放概率。我们的主要发现是IP3R1的钟形开放概率对这些调节结合位点的相对强度提供了约束。特别是,我们认为一个特定的Ca结合位点，其职能尚未确立，很可能是通道拮抗剂。此外,我们应用我们的模型来显示相邻亚基之间的域-域相互作用对通道协同性施加控制，并指示通道对Ca浓度的非线性响应。这表明特定的域-域相互作用在维持通道的稳定性中起着关键作用，这些相互作用的破坏可能是与Ca失调相关的疾病状态的基础。
