Molecular mechanism of GPCR spatial organization at the plasma membrane
Molecular mechanism of GPCR spatial organization at the plasma membrane
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DOI：
10.1038/s41589-023-01385-4
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发表时间：
2023-07-17
影响因子：
14.8
通讯作者：
Stamou，Dimitrios
中科院分区：
文献类型：
--
作者：
Kockelkoren，Gabriele;Lauritsen，Line;Stamou，Dimitrios
G蛋白偶联受体（GPCR）介导许多重要的生理过程。它们在质膜（PM）结构域中的空间组织被认为编码信号传导特异性和效率。然而，结构域的存在，关键是，这种推定的结构域的形成机制仍然难以捉摸。在这里，活细胞成像（校正地形诱导的成像伪影）最终建立了PM域的存在GPCR。巧合的是，与极浅PM曲率（<1 µm−1）的能量耦合成为GPCR时空组织的主导、必要和充分的分子机制。不同的GPCR，H-Ras，Piezo 1和表皮生长因子受体的实验表明，该机制是一般的，但蛋白质特异性，并可以通过配体调节。这些发现描绘了一种新的空间力学分子机制，可以将任何影响PM形态的机械或化学刺激转化为基于结构域的信号传导，并提出了针对细胞形状的创新治疗策略。
G-protein-coupled receptors (GPCRs) mediate many critical physiological processes. Their spatial organization in plasma membrane (PM) domains is believed to encode signaling specificity and efficiency. However, the existence of domains and, crucially, the mechanism of formation of such putative domains remain elusive. Here, live-cell imaging (corrected for topography-induced imaging artifacts) conclusively established the existence of PM domains for GPCRs. Paradoxically, energetic coupling to extremely shallow PM curvature (<1 µm−1) emerged as the dominant, necessary and sufficient molecular mechanism of GPCR spatiotemporal organization. Experiments with different GPCRs, H-Ras, Piezo1 and epidermal growth factor receptor, suggest that the mechanism is general, yet protein specific, and can be regulated by ligands. These findings delineate a new spatiomechanical molecular mechanism that can transduce to domain-based signaling any mechanical or chemical stimulus that affects the morphology of the PM and suggest innovative therapeutic strategies targeting cellular shape.