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Expansion of Intrinsically Disordered Proteins Increases the Range of Stability of Liquid-Liquid Phase Separation.

Authors
  • Garaizar, Adiran1
  • Sanchez-Burgos, Ignacio1
  • Collepardo-Guevara, Rosana1, 2, 3
  • Espinosa, Jorge R1
  • 1 Maxwell Centre, Cavendish Laboratory, Department of Physics, University of Cambridge, J J Thomson Avenue, Cambridge CB3 0HE, UK.
  • 2 Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
  • 3 Department of Genetics, University of Cambridge, Downing Site, Cambridge CB2 3EJ, UK.
Type
Published Article
Journal
Molecules
Publisher
MDPI AG
Publication Date
Oct 15, 2020
Volume
25
Issue
20
Identifiers
DOI: 10.3390/molecules25204705
PMID: 33076213
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Proteins containing intrinsically disordered regions (IDRs) are ubiquitous within biomolecular condensates, which are liquid-like compartments within cells formed through liquid-liquid phase separation (LLPS). The sequence of amino acids of a protein encodes its phase behaviour, not only by establishing the patterning and chemical nature (e.g., hydrophobic, polar, charged) of the various binding sites that facilitate multivalent interactions, but also by dictating the protein conformational dynamics. Besides behaving as random coils, IDRs can exhibit a wide-range of structural behaviours, including conformational switching, where they transition between alternate conformational ensembles. Using Molecular Dynamics simulations of a minimal coarse-grained model for IDRs, we show that the role of protein conformation has a non-trivial effect in the liquid-liquid phase behaviour of IDRs. When an IDR transitions to a conformational ensemble enriched in disordered extended states, LLPS is enhanced. In contrast, IDRs that switch to ensembles that preferentially sample more compact and structured states show inhibited LLPS. This occurs because extended and disordered protein conformations facilitate LLPS-stabilising multivalent protein-protein interactions by reducing steric hindrance; thereby, such conformations maximize the molecular connectivity of the condensed liquid network. Extended protein configurations promote phase separation regardless of whether LLPS is driven by homotypic and/or heterotypic protein-protein interactions. This study sheds light on the link between the dynamic conformational plasticity of IDRs and their liquid-liquid phase behaviour.

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