Conflicting Interfacial Electrostatic Interactions as a Design Principle to Modulate Long-Range Interdomain Communication

IF 3.8 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Bio & Med Chem Au Pub Date : 2023-11-07 DOI:10.1021/acsbiomedchemau.3c00047
Adithi Kannan, Dhruv Kumar Chaurasiya and Athi N. Naganathan*, 
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Abstract

The extent and molecular basis of interdomain communication in multidomain proteins, central to understanding allostery and function, is an open question. One simple evolutionary strategy could involve the selection of either conflicting or favorable electrostatic interactions across the interface of two closely spaced domains to tune the magnitude of interdomain connectivity. Here, we study a bilobed domain FF34 from the eukaryotic p190A RhoGAP protein to explore one such design principle that mediates interdomain communication. We find that while the individual structural units in wild-type FF34 are marginally coupled, they exhibit distinct intrinsic stabilities and low cooperativity, manifesting as slow folding. The FF3-FF4 interface harbors a frustrated network of highly conserved electrostatic interactions─a charge troika─that promotes the population of multiple, decoupled, and non-native structural modes on a rugged native landscape. Perturbing this network via a charge-reversal mutation not only enhances stability and cooperativity but also dampens the fluctuations globally and speeds up the folding rate by at least an order of magnitude. Our work highlights how a conserved but nonoptimal network of interfacial electrostatic interactions shapes the native ensemble of a bilobed protein, a feature that could be exploited in designing molecular systems with long-range connectivity and enhanced cooperativity.

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将相互冲突的界面静电相互作用作为调制远距离域间通讯的设计原则
多结构域蛋白质的结构域间通信是理解异构和功能的核心,其程度和分子基础是一个悬而未决的问题。一种简单的进化策略可能是在两个间隔较近的结构域界面上选择相互冲突或有利的静电相互作用,以调整结构域间连接的程度。在这里,我们研究了真核生物 p190A RhoGAP 蛋白的双叶结构域 FF34,以探索这种介导域间通讯的设计原理。我们发现,虽然野生型 FF34 中的单个结构单元略有耦合,但它们表现出不同的内在稳定性和低合作性,表现为缓慢折叠。FF3-FF4 界面蕴藏着一个由高度保守的静电相互作用组成的受挫网络--电荷三驾马车--它在崎岖不平的原生景观上促进了多重、解耦和非原生结构模式的群体。通过电荷反转突变来扰动这一网络,不仅能增强稳定性和合作性,还能抑制全局波动,并将折叠速度加快至少一个数量级。我们的研究突显了一个保守但非最佳的界面静电相互作用网络是如何塑造双叶蛋白的原生组合的,这一特征可用于设计具有长程连接性和更强合作性的分子系统。
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ACS Bio & Med Chem Au
ACS Bio & Med Chem Au 药物、生物、化学-
CiteScore
4.10
自引率
0.00%
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0
期刊介绍: ACS Bio & Med Chem Au is a broad scope open access journal which publishes short letters comprehensive articles reviews and perspectives in all aspects of biological and medicinal chemistry. Studies providing fundamental insights or describing novel syntheses as well as clinical or other applications-based work are welcomed.This broad scope includes experimental and theoretical studies on the chemical physical mechanistic and/or structural basis of biological or cell function in all domains of life. It encompasses the fields of chemical biology synthetic biology disease biology cell biology agriculture and food natural products research nucleic acid biology neuroscience structural biology and biophysics.The journal publishes studies that pertain to a broad range of medicinal chemistry including compound design and optimization biological evaluation molecular mechanistic understanding of drug delivery and drug delivery systems imaging agents and pharmacology and translational science of both small and large bioactive molecules. Novel computational cheminformatics and structural studies for the identification (or structure-activity relationship analysis) of bioactive molecules ligands and their targets are also welcome. The journal will consider computational studies applying established computational methods but only in combination with novel and original experimental data (e.g. in cases where new compounds have been designed and tested).Also included in the scope of the journal are articles relating to infectious diseases research on pathogens host-pathogen interactions therapeutics diagnostics vaccines drug-delivery systems and other biomedical technology development pertaining to infectious diseases.
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