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首页> 外文期刊>Developmental biology >Structure-function analysis of beta-arrestin Kurtz reveals a critical role of receptor interactions in downregulation of GPCR signaling in vivo
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Structure-function analysis of beta-arrestin Kurtz reveals a critical role of receptor interactions in downregulation of GPCR signaling in vivo

机译：Beta-Arcrectin Kurtz的结构功能分析显示受体相互作用在体内GPCR信号的下调中的关键作用

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摘要

Arrestins control signaling via the G protein coupled receptors (GPCRs), serving as both signal terminators and transducers. Previous studies identified several structural elements in arrestins that contribute to their functions as GPCR regulators. However, the importance of these elements in vivo is unclear, and the developmental roles of arrestins are not well understood. We carried out an in vivo structure-function analysis of Kurtz (Krz), the single ortholog of mammalian p-arrestins in the Drosophila genome. A combination of Krz mutations affecting the GPCR-phosphosensing and receptor core-binding ("finger loop") functions (Krz-KKVL/A) resulted in a complete loss of Krz activity during development. Endosome recruitment and bioluminescence resonance energy transfer (BRET) assays revealed that the KKVL/A mutations abolished the GPCR-binding ability of Krz. We found that the isolated "finger loop" mutation (Krz-VL/A), while having a negligible effect on GPCR internalization, severely affected Krz function, suggesting that tight receptor interactions are necessary for proper termination of signaling in vivo. Genetic analysis as well as live imaging demonstrated that mutations in Krz led to hyperactivity of the GPCR Mist (also known as Mthl1), which is activated by its ligand Folded gastrulation (Fog) and is responsible for cellular contractility and epithelial morphogenesis. Krz mutations affected two developmental events that are under the control of Fog-Mist signaling: gastrulation and morphogenesis of the wing. Overall, our data reveal the functional importance in vivo of direct beta-arrestin/GPCR binding, which is mediated by the recognition of the phosphorylated receptor tail and receptor core interaction. These Krz-GPCR interactions are critical for setting the correct level of Fog-Mist signaling during epithelial morphogenesis.
机译：通过G蛋白偶联受体（GPCR）控制信号传导，用作信号终端和换能器。以前的研究确定了逮捕者中的若干结构元素，这些元素有助于其作为GPCR监管机构的职能。然而，这些元素在体内的重要性尚不清楚，逮捕素的发育作用并不充分了解。我们对Kurtz（KRZ）进行了体内结构函数分析，在果蝇基因组中的哺乳动物P-increstins的单次垂直。影响GPCR-磷酸化和受体核心结合（“手指环”）功能（KRZ-KKVL / A）的KRZ突变的组合导致开发过程中的KRZ活性完全丧失。内体募集和生物发光共振能量转移（BRET）测定显示KKVL / A突变废除了KRZ的GPCR结合能力。我们发现分离的“手指环”突变（KRZ-VL / A），同时对GPCR内化具有可忽略的影响，严重影响KRZ功能，表明紧密的受体相互作用是正确终止在体内信号传导所必需的。遗传分析以及实时成像证明，KRZ中的突变导致GPCR雾的多动（也称为MTH1），其由其配体折叠的胃（雾）激活，并负责细胞收缩性和上皮形态发生。 KRZ突变影响了雾雾信号控制下的两种发育事件：机翼的腐蚀性和形态发生。总体而言，我们的数据揭示了直接β-arretIn / GPCR结合体内的功能重要性，其通过识别磷酸化受体尾部和受体核心相互作用来介导。这些KRZ-GPCR相互作用对于在上皮形态发生期间设定正确水平的雾雾信号传导至关重要。

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