小柯机器人

近日，美国加州大学旧金山分校Tanja Kortemme、Nevan J. Krogan等研究人员合作揭示异构扰动的系统级效应对一种模型分子开关的影响。这一研究成果于2021年10月13日在线发表在国际学术期刊《自然》上。

研究人员表示，分子开关蛋白在不同状态下的循环是由相反的调节因子控制的，这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中发挥作用，因此出现了一个基本问题：当不同的过程共享共同的调节因子时，如何实现功能的特异性。

研究人员发现，小GTP酶开关蛋白Gsp1（人类蛋白RAN的同源物）在酿酒酵母中的功能特异性与生物过程对Gsp1（RAN）开关周期的不同动力学敏感性有关。研究人员对Gsp1（RAN）的个别蛋白质相互作用界面进行了55次定向点突变，并通过定量遗传和物理相互作用图谱显示，Gsp1（RAN）界面的扰动具有广泛的细胞后果。与预期相反，接口突变的细胞效应是由其对GTP酶切换周期动力学参数的生物物理效应而不是由靶标接口来分组的。相反，结果表明，接口突变是对GTP酶周期动力学的异构调节。

这些结果提出了一个模型：蛋白质伴侣的结合或远端位点的翻译后修饰可以作为GTP酶切换的异构调节因子。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，这个能够确定分子扰动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影响。

附：英文原文

Title: Systems-level effects of allosteric perturbations to a model molecular switch

Author: Perica, Tina, Mathy, Christopher J. P., Xu, Jiewei, Jang, Gwendolyn ., Zhang, Yang, Kaake, Robyn, Ollikainen, Noah, Braberg, Hannes, Swaney, Danielle L., Lambright, David G., Kelly, Mark J. S., Krogan, Nevan J., Kortemme, Tanja

Issue&Volume: 2021-10-13

Abstract: Molecular switch proteins whose cycling between states is controlled by opposing regulators1,2 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.

DOI: 10.1038/s41586-021-03982-6

Source: https://www.nature.com/articles/s41586-021-03982-6

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