小柯机器人

德国莱比锡大学Tobias Langenhan和Nicole Scholz共同合作，近期取得重要工作进展。他们研究开发了机械和配体依赖性粘附GPCR解离的分子传感系统。相关论文2023年3月8日在线发表于《自然》杂志上。

据介绍，粘附G蛋白偶联受体 (aGPCR) 与Notch蛋白具有显著的相似性，Notch 蛋白是一类准备进行机械蛋白水解激活的表面受体，包括进化上保守的切割机制。 然而，到目前为止，还没有统一的解释为什么aGPCR是自蛋白水解处理的。

研究人员引入了一个基因编码的传感器系统来检测aGPCR异二聚体在其组成的N端和C端片段（分别为 NTF 和 CTF）中的解离事件。来自黑腹果蝇（Drosophila melanogaster）的神经 latrophilin 型 aGPCR Cirl (ADGRL) 的 NTF 释放传感器 (NRS) 受到机械力的刺激。Cirl-NRS激活表明受体解离发生在神经元和皮质神经胶质细胞中。从皮层神经胶质细胞释放NTF需要Cirl与其配体Toll 样受体Tollo (Toll-8) 在神经祖细胞上的反式相互作用，而顺式表达Cirl和Tollo会抑制aGPCR的解离。这种相互作用对于控制中枢神经系统中成神经细胞池的大小是必要的。

总之，研究人员得出结论，受体自身蛋白水解能够实现aGPCR的非细胞自主活动，并且aGPCR的解离受其配体表达谱和机械力控制。NRS系统将有助于阐明aGPCR的生理作用和信号调节剂，aGPCR构成了心血管、免疫、神经精神和肿瘤疾病的大量未开发药物靶标库。

附：英文原文

Title: Molecular sensing of mechano- and ligand-dependent adhesion GPCR dissociation

Author: Scholz, Nicole, Dahse, Anne-Kristin, Kemkemer, Marguerite, Bormann, Anne, Auger, Genevieve M., Vieira Contreras, Fernando, Ernst, Lucia F., Staake, Hauke, Krner, Marek B., Buhlan, Max, Meyer-Mlck, Amelie, Chung, Yin Kwan, Blanco-Redondo, Beatriz, Klose, Franziska, Jarboui, Mohamed Ali, Ljaschenko, Dmitrij, Bigl, Marina, Langenhan, Tobias

Issue&Volume: 2023-03-08

Abstract: Adhesion G-protein-coupled receptors (aGPCRs) bear notable similarity to Notch proteins1, a class of surface receptors poised for mechano-proteolytic activation2,3,4, including an evolutionarily conserved mechanism of cleavage5,6,7,8. However, so far there is no unifying explanation for why aGPCRs are autoproteolytically processed. Here we introduce a genetically encoded sensor system to detect the dissociation events of aGPCR heterodimers into their constituent N-terminal and C-terminal fragments (NTFs and CTFs, respectively). An NTF release sensor (NRS) of the neural latrophilin-type aGPCR Cirl (ADGRL)9,10,11, from Drosophila melanogaster, is stimulated by mechanical force. Cirl-NRS activation indicates that receptor dissociation occurs in neurons and cortex glial cells. The release of NTFs from cortex glial cells requires trans-interaction between Cirl and its ligand, the Toll-like receptor Tollo (Toll-8)12, on neural progenitor cells, whereas expressing Cirl and Tollo in cis suppresses dissociation of the aGPCR. This interaction is necessary to control the size of the neuroblast pool in the central nervous system. We conclude that receptor autoproteolysis enables non-cell-autonomous activities of aGPCRs, and that the dissociation of aGPCRs is controlled by their ligand expression profile and by mechanical force. The NRS system will be helpful in elucidating the physiological roles and signal modulators of aGPCRs, which constitute a large untapped reservoir of drug targets for cardiovascular, immune, neuropsychiatric and neoplastic diseases13.

DOI: 10.1038/s41586-023-05802-5

Source: https://www.nature.com/articles/s41586-023-05802-5

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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