RT Journal Article
SR Electronic
T1 Sequence grammar underlying unfolding and phase separation of globular proteins
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.08.20.457073
DO 10.1101/2021.08.20.457073
A1 Ruff, Kiersten M.
A1 Choi, Yoon Hee
A1 Cox, Dezerae
A1 Ormsby, Angelique R.
A1 Myung, Yoochan
A1 Ascher, David B.
A1 Radford, Sheena E.
A1 Pappu, Rohit V.
A1 Hatters, Danny M.
YR 2022
UL http://biorxiv.org/content/early/2022/05/06/2021.08.20.457073.abstract
AB 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.HighlightsUnfolded states of globular proteins phase separate to form UPODs in cellsThe fraction of unfolded molecules and the sticker grammar govern phase separationHydrophobic residues act as stickers that engage in intermolecular interactionsSticker grammar also influences gain-of-function recruitment into aberrant UPODsCompeting Interest StatementThe authors have declared no competing interest.