Condensed-phase signaling can expand kinase specificity and respond to macromolecular crowding.
Condensed-phase signaling can expand kinase specificity and respond to macromolecular crowding.
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DOI：
10.1016/j.molcel.2022.08.016
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发表时间：
2022-10-06
期刊：
影响因子：
16
通讯作者：
Holt, Liam J.
中科院分区：
文献类型：
--
作者：
Sang, Dajun;Shu, Tong;Pantoja, Christian F.;de Opakua, Alain Ibanez;Zweckstetter, Markus;Holt, Liam J.
相分离可以浓缩生物分子并加速反应。然而，由于与破坏内源性凝聚物相关的多效性效应，将这种中尺度组织与信号动力学联系起来的机制和原理很难剖析。为了解决这一限制，我们在合成缩合物中设计了新的磷酸化反应。我们通常发现活性增加并扩大了激酶特异性。凝聚物内的磷酸化动力学很快，可以驱动细胞周期依赖性定位变化。冷凝物中的高客户浓度很重要，但不是有效磷酸化的主要因素。相反，许多多余的客户结合位点和灵活的支架的可用性至关重要。缩合物内的磷酸化也受到大分子拥挤变化的调节。最后，细胞周期蛋白依赖性激酶 2 对阿尔茨海默病相关蛋白 Tau 的磷酸化在凝聚物中加速。因此，冷凝物可以实现新的信号连接，并可以创建对细胞质的生物物理特性做出反应的传感器。桑等人。利用合成生物学证明相分离的生物分子缩合物可以增强激酶信号传导。合成冷凝物可以系统地探索有效信号传导和对生物物理线索的响应所需的特征。最后，相分离加速了阿尔茨海默病相关的磷酸化事件。
Phase separation can concentrate biomolecules and accelerate reactions. However, the mechanisms and principles connecting this mesoscale organization to signaling dynamics are difficult to dissect because of the pleiotropic effects associated with disrupting endogenous condensates. To address this limitation, we engineered new phosphorylation reactions within synthetic condensates. We generally found increased activity and broadened kinase specificity. Phosphorylation dynamics within condensates were rapid and could drive cell-cycle-dependent localization changes. High client concentration within condensates was important but not the main factor for efficient phosphorylation. Rather, the availability of many excess client-binding sites together with a flexible scaffold was crucial. Phosphorylation within condensates was also modulated by changes in macromolecular crowding. Finally, the phosphorylation of the Alzheimer’s-disease-associated protein Tau by cyclin-dependent kinase 2 was accelerated within condensates. Thus, condensates enable new signaling connections and can create sensors that respond to the biophysical properties of the cytoplasm. Sang et al. use synthetic biology to demonstrate that phase-separated biomolecular condensates can potentiate kinase signaling. Synthetic condensates allow the systematic exploration of features required for efficient signaling and responsiveness to biophysical cues. Finally, phase separation accelerates Alzheimer’s-associated phosphorylation events.
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影响因子：
7.3
作者：
Alexander J;Lim D;Joughin BA;Hegemann B;Hutchins JR;Ehrenberger T;Ivins F;Sessa F;Hudecz O;Nigg EA;Fry AM;Musacchio A;Stukenberg PT;Mechtler K;Peters JM;Smerdon SJ;Yaffe MB
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Yaffe MB
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21.3
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2.3
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通讯作者：
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影响因子：
16.6
作者：
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通讯作者：
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影响因子：
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作者：
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