A conformational switch driven by phosphorylation regulates the activity of the evolutionarily conserved SNARE Ykt6.
A conformational switch driven by phosphorylation regulates the activity of the evolutionarily conserved SNARE Ykt6.
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DOI：
10.1073/pnas.2016730118
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发表时间：
2021-03-23
影响因子：
11.1
通讯作者：
Caraveo G
中科院分区：
文献类型：
--
作者：
McGrath K;Agarwal S;Tonelli M;Dergai M;Gaeta AL;Shum AK;Lacoste J;Zhang Y;Wen W;Chung D;Wiersum G;Shevade A;Zaichick S;van Rossum DB;Shuvalova L;Savas JN;Kuchin S;Taipale M;Caldwell KA;Caldwell GA;Fasshauer D;Caraveo G
Ykt 6是一个保守的SNARE，在沿着多个囊泡途径中发挥关键作用。为了实现其功能，Ykt 6通过可逆的脂化在细胞质和膜结合区室之间循环。调节这些转变的机制尚不清楚。Ykt 6的功能被α-突触核蛋白破坏，α-突触核蛋白是一种与突触核蛋白病如帕金森病密切相关的蛋白质。通过多学科的方法，我们报告说，磷酸化调节Ca 2+信号驱动的构象变化，使Ykt 6开关从一个封闭的胞质到一个开放的膜结合的形式。磷酸化也是Ykt 6蛋白相互作用的关键决定因素，在正常和α-突触核蛋白条件下，在分泌和自噬途径中产生功能后果。这项工作提供了一个机制的洞察Ykt 6调节与治疗意义的突触核蛋白病。Ykt 6是一种可溶性N-乙基马来酰亚胺敏感因子激活蛋白受体（SNARE），在多种囊泡融合途径中发挥重要作用。虽然大多数SNARE依赖于跨膜结构域的活性，Ykt 6动态循环之间的胞质溶胶和膜结合区室，它是活跃的。调节这些转变并允许Ykt 6实现对囊泡途径的特异性的机制尚不清楚。使用帕金森病（PD）模型，我们发现Ykt 6是磷酸化的进化保守的网站，这是由Ca 2+信号调节。通过多学科的方法，我们表明，磷酸化触发的构象变化，使Ykt 6从一个封闭的胞质切换到一个开放的膜结合的形式。在磷酸化开放形式中，蛋白质相互作用的谱发生变化，导致分泌和自噬途径的缺陷，增强PD模型的毒性。我们的研究揭示了一种机制，Ykt 6构象和活性的调节与PD的潜在影响。
Ykt6 is a conserved SNARE that plays critical roles along multiple vesicular pathways. To achieve its function, Ykt6 cycles between the cytosol and membrane-bound compartments through reversible lipidation. The mechanism that regulates these transitions is unknown. Ykt6 function is disrupted by α-synuclein, a protein critically implicated in synucleinopathies such as Parkinson’s Disease. Through a multidisciplinary approach, we report that phosphorylation regulated by Ca2+ signaling drives a conformational change that allows Ykt6 to switch from a closed cytosolic to an open membrane-bound form. Phosphorylation is also a critical determinant for Ykt6 protein interactions with functional consequences in the secretory and autophagy pathways under normal and α-synuclein conditions. This work provides a mechanistic insight into Ykt6 regulation with therapeutic implications for synucleinopathies. Ykt6 is a soluble N-ethylmaleimide sensitive factor activating protein receptor (SNARE) critically involved in diverse vesicular fusion pathways. While most SNAREs rely on transmembrane domains for their activity, Ykt6 dynamically cycles between the cytosol and membrane-bound compartments where it is active. The mechanism that regulates these transitions and allows Ykt6 to achieve specificity toward vesicular pathways is unknown. Using a Parkinson’s disease (PD) model, we found that Ykt6 is phosphorylated at an evolutionarily conserved site which is regulated by Ca2+ signaling. Through a multidisciplinary approach, we show that phosphorylation triggers a conformational change that allows Ykt6 to switch from a closed cytosolic to an open membrane-bound form. In the phosphorylated open form, the spectrum of protein interactions changes, leading to defects in both the secretory and autophagy pathways, enhancing toxicity in PD models. Our studies reveal a mechanism by which Ykt6 conformation and activity are regulated with potential implications for PD.
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DOI：
10.1534/g3.115.019174
发表时间：
2015-07-14
期刊：
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影响因子：
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发表时间：
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影响因子：
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作者：
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