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Molecular determinants and signaling effects of PKA RIα phase separation.
Hardy, Julia C; Pool, Emily H; Bruystens, Jessica G H; Zhou, Xin; Li, Qingrong; Zhou, Daojia R; Palay, Max; Tan, Gerald; Chen, Lisa; Choi, Jaclyn L C; Lee, Ha Neul; Strack, Stefan; Wang, Dong; Taylor, Susan S; Mehta, Sohum; Zhang, Jin.
Afiliación
  • Hardy JC; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
  • Pool EH; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
  • Bruystens JGH; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
  • Zhou X; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
  • Li Q; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • Zhou DR; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
  • Palay M; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
  • Tan G; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
  • Chen L; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
  • Choi JLC; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
  • Lee HN; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
  • Strack S; Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA.
  • Wang D; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
  • Taylor SS; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
  • Mehta S; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA.
  • Zhang J; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Shu Chien-Gene Lay Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093,
Mol Cell ; 84(8): 1570-1584.e7, 2024 Apr 18.
Article en En | MEDLINE | ID: mdl-38537638
ABSTRACT
Spatiotemporal regulation of intracellular signaling molecules, such as the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), ensures proper cellular function. Liquid-liquid phase separation (LLPS) of the ubiquitous PKA regulatory subunit RIα promotes cAMP compartmentation and signaling specificity. However, the molecular determinants of RIα LLPS remain unclear. Here, we reveal that two separate dimerization interfaces, combined with the cAMP-induced unleashing of the PKA catalytic subunit (PKA-C) from the pseudosubstrate inhibitory sequence, drive RIα condensate formation in the cytosol of mammalian cells, which is antagonized by docking to A-kinase anchoring proteins. Strikingly, we find that the RIα pseudosubstrate region is critically involved in forming a non-canonical RC complex, which recruits active PKA-C to RIα condensates to maintain low basal PKA activity in the cytosol. Our results suggest that RIα LLPS not only facilitates cAMP compartmentation but also spatially restrains active PKA-C, thus highlighting the functional versatility of biomolecular condensates in driving signaling specificity.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico / Separación de Fases Límite: Animals Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Subunidad RIalfa de la Proteína Quinasa Dependiente de AMP Cíclico / Separación de Fases Límite: Animals Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos