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Competing stress-dependent oligomerization pathways regulate self-assembly of the periplasmic protease-chaperone DegP.
Harkness, Robert W; Toyama, Yuki; Ripstein, Zev A; Zhao, Huaying; Sever, Alexander I M; Luan, Qing; Brady, Jacob P; Clark, Patricia L; Schuck, Peter; Kay, Lewis E.
Afiliación
  • Harkness RW; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada; r.harkness@utoronto.ca kay@pound.med.utoronto.ca.
  • Toyama Y; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Ripstein ZA; Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada.
  • Zhao H; Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada.
  • Sever AIM; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Luan Q; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Brady JP; Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada.
  • Clark PL; Program in Molecular Medicine, The Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada.
  • Schuck P; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Kay LE; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Proc Natl Acad Sci U S A ; 118(32)2021 08 10.
Article en En | MEDLINE | ID: mdl-34362850
DegP is an oligomeric protein with dual protease and chaperone activity that regulates protein homeostasis and virulence factor trafficking in the periplasm of gram-negative bacteria. A number of oligomeric architectures adopted by DegP are thought to facilitate its function. For example, DegP can form a "resting" hexamer when not engaged to substrates, mitigating undesired proteolysis of cellular proteins. When bound to substrate proteins or lipid membranes, DegP has been shown to populate a variety of cage- or bowl-like oligomeric states that have increased proteolytic activity. Though a number of DegP's substrate-engaged structures have been robustly characterized, detailed mechanistic information underpinning its remarkable oligomeric plasticity and the corresponding interplay between these dynamics and biological function has remained elusive. Here, we have used a combination of hydrodynamics and NMR spectroscopy methodologies in combination with cryogenic electron microscopy to shed light on the apo-DegP self-assembly mechanism. We find that, in the absence of bound substrates, DegP populates an ensemble of oligomeric states, mediated by self-assembly of trimers, that are distinct from those observed in the presence of substrate. The oligomeric distribution is sensitive to solution ionic strength and temperature and is shifted toward larger oligomeric assemblies under physiological conditions. Substrate proteins may guide DegP toward canonical cage-like structures by binding to these preorganized oligomers, leading to changes in conformation. The properties of DegP self-assembly identified here suggest that apo-DegP can rapidly shift its oligomeric distribution in order to respond to a variety of biological insults.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Serina Endopeptidasas / Proteínas Periplasmáticas / Proteínas de Choque Térmico Tipo de estudio: Prognostic_studies Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Serina Endopeptidasas / Proteínas Periplasmáticas / Proteínas de Choque Térmico Tipo de estudio: Prognostic_studies Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2021 Tipo del documento: Article Pais de publicación: Estados Unidos