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Human and Bacterial Toll-Interleukin Receptor Domains Exhibit Distinct Dynamic Features and Functions.
Lee, Eunjeong; Redzic, Jasmina S; Nemkov, Travis; Saviola, Anthony J; Dzieciatkowska, Monika; Hansen, Kirk C; D'Alessandro, Angelo; Dinarello, Charles; Eisenmesser, Elan Z.
Afiliación
  • Lee E; Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, 12801 E 17th Ave, Aurora, CO 80045, USA.
  • Redzic JS; Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, 12801 E 17th Ave, Aurora, CO 80045, USA.
  • Nemkov T; Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, 12801 E 17th Ave, Aurora, CO 80045, USA.
  • Saviola AJ; Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, 12801 E 17th Ave, Aurora, CO 80045, USA.
  • Dzieciatkowska M; Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, 12801 E 17th Ave, Aurora, CO 80045, USA.
  • Hansen KC; Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, 12801 E 17th Ave, Aurora, CO 80045, USA.
  • D'Alessandro A; Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Anschutz Medical Campus, 12801 E 17th Ave, Aurora, CO 80045, USA.
  • Dinarello C; Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, 12801 E 17th Ave, Aurora, CO 80045, USA.
  • Eisenmesser EZ; Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
Molecules ; 27(14)2022 Jul 14.
Article en En | MEDLINE | ID: mdl-35889366
Toll-interleukin receptor (TIR) domains have emerged as critical players involved in innate immune signaling in humans but are also expressed as potential virulence factors within multiple pathogenic bacteria. However, there has been a shortage of structural studies aimed at elucidating atomic resolution details with respect to their interactions, potentially owing to their dynamic nature. Here, we used a combination of biophysical and biochemical studies to reveal the dynamic behavior and functional interactions of a panel of both bacterial TIR-containing proteins and mammalian receptor TIR domains. Regarding dynamics, all three bacterial TIR domains studied here exhibited an inherent exchange that led to severe resonance line-broadening, revealing their intrinsic dynamic nature on the intermediate NMR timescale. In contrast, the three mammalian TIR domains studied here exhibited a range in terms of their dynamic exchange that spans multiple timescales. Functionally, only the bacterial TIR domains were catalytic towards the cleavage of NAD+, despite the conservation of the catalytic nucleophile on human TIR domains. Our development of NMR-based catalytic assays allowed us to further identify differences in product formation for gram-positive versus gram-negative bacterial TIR domains. Differences in oligomeric interactions were also revealed, whereby bacterial TIR domains self-associated solely through their attached coil-coil domains, in contrast to the mammalian TIR domains that formed homodimers and heterodimers through reactive cysteines. Finally, we provide the first atomic-resolution studies of a bacterial coil-coil domain and provide the first atomic model of the TIR domain from a human anti-inflammatory IL-1R8 protein that undergoes a slow inherent exchange.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Bacterias / Factores de Virulencia Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Molecules Asunto de la revista: BIOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Bacterias / Factores de Virulencia Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Molecules Asunto de la revista: BIOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza