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

Bartosz Gabryelczyk, Hao Cai, Xiangyan Shi, Yue Sun, Piet J. M. Swinkels, Stefan Salentinig, Konstantin Pervushin () and Ali Miserez ()
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Bartosz Gabryelczyk: Nanyang Technological University (NTU)
Hao Cai: Nanyang Technological University (NTU)
Xiangyan Shi: School of Physical and Mathematical Sciences
Yue Sun: Nanyang Technological University (NTU)
Piet J. M. Swinkels: Nanyang Technological University (NTU)
Stefan Salentinig: Laboratory for Biointerfaces, Department Materials Meet Life, EMPA
Konstantin Pervushin: School of Biological Sciences
Ali Miserez: Nanyang Technological University (NTU)

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-13469-8

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