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Atomic resolution map of the solvent interactions driving SOD1 unfolding in CAPRIN1 condensates.
Ahmed, Rashik; Liang, Mingyang; Hudson, Rhea P; Rangadurai, Atul K; Huang, Shuya Kate; Forman-Kay, Julie D; Kay, Lewis E.
Afiliación
  • Ahmed R; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Liang M; Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada.
  • Hudson RP; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Rangadurai AK; Program in Molecular Medicine, Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada.
  • Huang SK; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Forman-Kay JD; Program in Molecular Medicine, Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada.
  • Kay LE; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Proc Natl Acad Sci U S A ; 121(35): e2408554121, 2024 Aug 27.
Article en En | MEDLINE | ID: mdl-39172789
ABSTRACT
Biomolecules can be sequestered into membrane-less compartments, referred to as biomolecular condensates. Experimental and computational methods have helped define the physical-chemical properties of condensates. Less is known about how the high macromolecule concentrations in condensed phases contribute "solvent" interactions that can remodel the free-energy landscape of other condensate-resident proteins, altering thermally accessible conformations and, in turn, modulating function. Here, we use solution NMR spectroscopy to obtain atomic resolution insights into the interactions between the immature form of superoxide dismutase 1 (SOD1), which can mislocalize and aggregate in stress granules, and the RNA-binding protein CAPRIN1, a component of stress granules. NMR studies of CAPRIN1SOD1 interactions, focused on both unfolded and folded SOD1 states in mixed phase and demixed CAPRIN1-based condensates, establish that CAPRIN1 shifts the SOD1 folding equilibrium toward the unfolded state through preferential interactions with the unfolded ensemble, with little change to the structure of the folded conformation. Key contacts between CAPRIN1 and the H80-H120 region of unfolded SOD1 are identified, as well as SOD1 interaction sites near both the arginine-rich and aromatic-rich regions of CAPRIN1. Unfolding of immature SOD1 in the CAPRIN1 condensed phase is shown to be coupled to aggregation, while a more stable zinc-bound, dimeric form of SOD1 is less susceptible to unfolding when solvated by CAPRIN1. Our work underscores the impact of the condensate solvent environment on the conformational states of resident proteins and supports the hypothesis that ALS mutations that decrease metal binding or dimerization function as drivers of aggregation in condensates.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Solventes / Superóxido Dismutasa-1 Límite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2024 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Solventes / Superóxido Dismutasa-1 Límite: Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2024 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos