Sequence Grammar Underlying the Unfolding and Phase Separation of Globular Proteins

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2022 Jul 19

PMID 35853451

Authors

Kiersten M Ruff

Yoon Hee Choi

Dezerae Cox

Angelique R Ormsby

Yoochan Myung

David B Ascher

Sheena E Radford

Rohit V Pappu

Danny M Hatters

Affiliations

Soon will be listed here.

Abstract

Aberrant phase separation of globular proteins is associated with many diseases. Here, we use a model protein system to understand how the unfolded states of globular proteins drive phase separation and the formation of unfolded protein deposits (UPODs). We find that for UPODs to form, the concentrations of unfolded molecules must be above a threshold value. Additionally, unfolded molecules must possess appropriate sequence grammars to drive phase separation. While UPODs recruit molecular chaperones, their compositional profiles are also influenced by synergistic physicochemical interactions governed by the sequence grammars of unfolded proteins and cellular proteins. Overall, the driving forces for phase separation and the compositional profiles of UPODs are governed by the sequence grammars of unfolded proteins. Our studies highlight the need for uncovering the sequence grammars of unfolded proteins that drive UPOD formation and cause gain-of-function interactions whereby proteins are aberrantly recruited into UPODs.

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