Sequence grammar underlying the unfolding and phase separation of globular proteins

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

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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.

Original languageEnglish
Pages (from-to)3193-3208.e8
JournalMolecular cell
Volume82
Issue number17
DOIs
StatePublished - Sep 1 2022

Keywords

  • Cry2
  • SOD1
  • TRiC
  • barnase
  • chaperonin-containing T-complex
  • molecular condensate
  • protein deposit
  • protein folding
  • protein misfolding
  • protein quality control
  • proteostasis
  • superoxide dismutase 1

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