Pi-Pi contacts are an overlooked protein feature relevant to phase separation

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Abstract

Protein phase separation is implicated in formation of membraneless organelles, signaling puncta and the nuclear pore. Multivalent interactions of modular binding domains and their target motifs can drive phase separation. However, forces promoting the more common phase separation of intrinsically disordered regions are less understood, with suggested roles for multivalent cation-pi, pi-pi, and charge interactions and the hydrophobic effect. Known phase-separating proteins are enriched in pi-orbital containing residues and thus we analyzed pi-interactions in folded proteins. We found that pi-pi interactions involving non-aromatic groups are widespread, underestimated by force-fields used in structure calculations and correlated with solvation and lack of regular secondary structure, properties associated with disordered regions. We present a phase separation predictive algorithm based on pi interaction frequency, highlighting proteins involved in biomaterials and RNA processing.

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Article and author information

Author details

Robert McCoy Vernon

Program in Molecular Medicine, Hospital for Sick Children, Toronto, Canada

Competing interests
The authors declare that no competing interests exist.
Paul Andrew Chong

Program in Molecular Medicine, Hospital for Sick Children, Toronto, Canada

Competing interests
The authors declare that no competing interests exist.
Brian Tsang

Program in Molecular Medicine, Hospital for Sick Children, Toronto, Canada

Competing interests
The authors declare that no competing interests exist.
Tae Hun Kim

Program in Molecular Medicine, Hospital for Sick Children, Toronto, Canada

Competing interests
The authors declare that no competing interests exist.
Alaji Bah

Program in Molecular Medicine, Hospital for Sick Children, Toronto, Canada

Competing interests
The authors declare that no competing interests exist.
Patrick Farber

Program in Molecular Medicine, Hospital for Sick Children, Toronto, Canada

Competing interests
The authors declare that no competing interests exist.
Hong Lin

Program in Molecular Medicine, Hospital for Sick Children, Toronto, Canada

Competing interests
The authors declare that no competing interests exist.
Julie Deborah Forman-Kay

Program in Molecular Medicine, Hospital for Sick Children, Toronto, Canada

For correspondence
forman@sickkids.ca

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-8265-972X

Funding

Canadian Institutes of Health Research (114985)

Julie Deborah Forman-Kay

Natural Sciences and Engineering Research Council of Canada (6718)

Julie Deborah Forman-Kay

Canadian Cancer Society Research Institute (703477)

Julie Deborah Forman-Kay

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.