Department of Molecular Biosciences, Northwestern University, Evanston, IL, 60208, USA.
Nat Commun. 2022 Apr 22;13(1):2194. doi: 10.1038/s41467-022-29897-y.
Transfer of information across membranes is fundamental to the function of all organisms and is primarily initiated by transmembrane receptors. For many receptors, how ligand sensitivity is fine-tuned and how disease associated mutations modulate receptor conformation to allosterically affect receptor sensitivity are unknown. Here we map the activation of the calcium-sensing receptor (CaSR) - a dimeric class C G protein-coupled receptor (GPCR) and responsible for maintaining extracellular calcium in vertebrates. We show that CaSR undergoes unique conformational rearrangements compared to other class C GPCRs owing to specific structural features. Moreover, by analyzing disease associated mutations, we uncover a large permissiveness in the architecture of the extracellular domain of CaSR, with dynamics- and not specific receptor topology- determining the effect of a mutation. We show a structural hub at the dimer interface allosterically controls CaSR activation via focused electrostatic repulsion. Changes in the surface charge distribution of this hub, which is highly variable between organisms, finely tune CaSR sensitivity. This is potentially a general tuning mechanism for other dimeric receptors.
跨膜信息传递是所有生物体功能的基础，主要由跨膜受体启动。对于许多受体，配体敏感性如何被微调，以及与疾病相关的突变如何改变受体构象以变构影响受体敏感性，这些都不清楚。在这里，我们绘制了钙敏感受体 (CaSR) 的激活图——一种二聚体 C 类 G 蛋白偶联受体 (GPCR)，负责维持脊椎动物细胞外钙。我们表明，由于特定的结构特征，CaSR 经历了与其他 C 类 GPCR 相比独特的构象重排。此外，通过分析与疾病相关的突变，我们揭示了 CaSR 细胞外结构域的结构具有很大的可容纳性，动态而不是特定的受体拓扑结构决定了突变的影响。我们显示二聚体界面上的结构枢纽通过集中的静电排斥作用变构控制 CaSR 的激活。该枢纽的表面电荷分布发生变化，在不同生物体之间高度可变，精细地调节 CaSR 的敏感性。这可能是其他二聚体受体的一般调节机制。
