Summary
Aberrant phase separation of globular proteins is associated with many diseases. Here, we use a model protein system to understand how unfolded states of globular proteins drive phase separation and the formation of unfolded protein deposits (UPODs). 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 sequence features of cellular proteins. Overall, we find that the driving forces for phase separation and the compositional profiles of UPODs are governed by the sequence grammar of unfolded proteins. Our studies highlight the need for uncovering the sequence grammars of unfolded proteins that drive UPOD formation and lead to gain-of-function interactions whereby proteins are aberrantly recruited into UPODs.
Highlights
Unfolded states of globular proteins phase separate to form UPODs in cells
The fraction of unfolded molecules and the sticker grammar govern phase separation
Hydrophobic residues act as stickers that engage in intermolecular interactions
Sticker grammar also influences gain-of-function recruitment into aberrant UPODs
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
The manuscript has been revised extensively in response to comments from reviewers. New data on the compositional profiles of UPODs have been included.
