Hydrogen bond guidance and aromatic stacking drive liquid-liquid phase separation of intrinsically disordered histidine-rich peptides.,Nature Communications

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Hydrogen bond guidance and aromatic stacking drive liquid-liquid phase separation of intrinsically disordered histidine-rich peptides.
Nature Communications ( IF 14.7 ) Pub Date : 2019-11-29 , DOI: 10.1038/s41467-019-13469-8
Bartosz Gabryelczyk _{1,

2} , Hao Cai ₁ , Xiangyan Shi ₃ , Yue Sun ₁ , Piet J M Swinkels _{1,

4} , Stefan Salentinig _{5,

6} , Konstantin Pervushin ₇ , Ali Miserez _{1,

7}

Affiliation

Liquid-liquid phase separation (LLPS) of intrinsically disordered proteins (IDPs) is involved in both intracellular membraneless organelles and extracellular tissues. Despite growing understanding of LLPS, molecular-level mechanisms behind this process are still not fully established. Here, we use histidine-rich squid beak proteins (HBPs) as model IDPs to shed light on molecular interactions governing LLPS. We show that LLPS of HBPs is mediated though specific modular repeats. The morphology of separated phases (liquid-like versus hydrogels) correlates with the repeats' hydrophobicity. Solution-state NMR indicates that LLPS is a multistep process initiated by deprotonation of histidine residues, followed by transient hydrogen bonding with tyrosine, and eventually by hydrophobic interactions. The microdroplets are stabilized by aromatic clustering of tyrosine residues exhibiting restricted molecular mobility in the nano-to-microsecond timescale according to solid-state NMR experiments. Our findings provide guidelines to rationally design pH-responsive peptides with LLPS ability for various applications, including bioinspired protocells and smart drug-delivery systems.

中文翻译：

氢键引导和芳族堆积驱动本质上无序的富含组氨酸的肽的液-液相分离。

固有紊乱蛋白（IDP）的液-液相分离（LLPS）参与细胞内无膜细胞器和细胞外组织。尽管人们对LLPS有越来越多的了解，但该过程背后的分子水平机制仍未完全建立。在这里，我们使用富含组氨酸的鱿鱼喙蛋白（HBP）作为模型IDP，以阐明控制LLPS的分子相互作用。我们显示HBPs的LLPS是通过特定的模块重复介导的。分离相的形态（液体状与水凝胶状）与重复序列的疏水性相关。溶液状态的NMR表明LLPS是一个多步过程，由组氨酸残基的去质子化，随后与酪氨酸的氢瞬时键合以及最终的疏水相互作用引发。根据固态NMR实验，微滴通过酪氨酸残基的芳香族聚团而稳定，酪氨酸残基在纳秒至微秒的时间范围内显示出受限的分子迁移率。我们的发现为合理设计具有LLPS功能的pH响应肽提供了指导，可用于各种应用，包括生物启发的原始细胞和智能药物递送系统。

更新日期：2019-11-30

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