Systems-level effects of allosteric perturbations to a model molecular switch,Nature

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Systems-level effects of allosteric perturbations to a model molecular switch
Nature ( IF 50.5 ) Pub Date : 2021-10-13 , DOI: 10.1038/s41586-021-03982-6
Tina Perica _{1,

2,

3} , Christopher J P Mathy _{1,

2,

4} , Jiewei Xu _{2,

5,

6} , Gwendolyn Μ Jang _{2,

5,

6} , Yang Zhang _{1,

2} , Robyn Kaake _{2,

5,

6} , Noah Ollikainen _{1,

2,

7} , Hannes Braberg _{2,

5,

6} , Danielle L Swaney _{2,

5,

6} , David G Lambright _{8,

9} , Mark J S Kelly ₁₀ , Nevan J Krogan _{2,

5,

6} , Tanja Kortemme _{1,

2,

4,

7,

11}

Affiliation

Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.
European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Cambridge, UK.
The UC Berkeley-UCSF Graduate Program in Bioengineering, University of California San Francisco, San Francisco, CA, USA.
Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
The J. David Gladstone Institutes, San Francisco, CA, USA.
Graduate Program in Bioinformatics, University of California San Francisco, San Francisco, California, USA.
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA.
Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
Chan Zuckerberg Biohub, San Francisco, CA, USA.

Molecular switch proteins whose cycling between states is controlled by opposing regulators^1,2 are central to biological signal transduction. As switch proteins function within highly connected interaction networks³, the fundamental question arises of how functional specificity is achieved when different processes share common regulators. Here we show that functional specificity of the small GTPase switch protein Gsp1 in Saccharomyces cerevisiae (the homologue of the human protein RAN)⁴ is linked to differential sensitivity of biological processes to different kinetics of the Gsp1 (RAN) switch cycle. We make 55 targeted point mutations to individual protein interaction interfaces of Gsp1 (RAN) and show through quantitative genetic⁵ and physical interaction mapping that Gsp1 (RAN) interface perturbations have widespread cellular consequences. Contrary to expectation, the cellular effects of the interface mutations group by their biophysical effects on kinetic parameters of the GTPase switch cycle and not by the targeted interfaces. Instead, we show that interface mutations allosterically tune the GTPase cycle kinetics. These results suggest a model in which protein partner binding, or post-translational modifications at distal sites, could act as allosteric regulators of GTPase switching. Similar mechanisms may underlie regulation by other GTPases, and other biological switches. Furthermore, our integrative platform to determine the quantitative consequences of molecular perturbations may help to explain the effects of disease mutations that target central molecular switches.

中文翻译：

变构扰动对模型分子开关的系统级影响

^{状态之间的循环由相反的调节器1,2}控制的分子开关蛋白是生物信号转导的核心。由于开关蛋白在高度连接的相互作用网络³中发挥作用，因此出现了一个基本问题，即当不同的过程共享共同的监管机构时如何实现功能特异性。在这里，我们表明酿酒酵母（人类蛋白质 RAN 的同系物）⁴中小 GTPase 开关蛋白 Gsp1 的功能特异性与生物过程对 Gsp1 (RAN) 开关周期不同动力学的不同敏感性有关。我们对 Gsp1 (RAN) 的单个蛋白质相互作用界面进行了 55 个靶向点突变，并通过定量遗传显示^5个Gsp1 (RAN) 接口扰动具有广泛的细胞后果的物理交互映射。与预期相反，界面突变的细胞效应通过它们对 GTPase 开关周期动力学参数的生物物理效应分组，而不是通过目标界面。相反，我们表明界面突变变构地调整 GTPase 循环动力学。这些结果表明了一个模型，其中蛋白质伴侣结合或远端位点的翻译后修饰可以充当 GTP 酶转换的变构调节剂。类似的机制可能是其他 GTP 酶和其他生物开关调节的基础。此外，我们用于确定分子扰动的定量后果的综合平台可能有助于解释针对中心分子开关的疾病突变的影响。

更新日期：2021-10-13

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