Conformational states of TNFR1 as a molecular switch for receptor function

Chih Hung Lo, Evan C. Huber, Jonathan N. Sachs

Research output: Contribution to journalArticle

Abstract

Tumor necrosis factor receptor 1 (TNFR1) is a transmembrane receptor that plays a key role in the regulation of the inflammatory pathway. While inhibition of TNFR1 has been the focus of many studies for the treatment of autoimmune diseases such as rheumatoid arthritis, activation of the receptor is important for the treatment of immunodeficiency diseases such as HIV and neurodegenerative diseases such as Alzheimer's disease where a boost in immune signaling is required. In addition, activation of other TNF receptors such as death receptor 5 or FAS receptor is important for cancer therapy. Here, we used a previously established TNFR1 fluorescence resonance energy transfer (FRET) biosensor together with a fluorescence lifetime technology as a high-throughput screening platform to identify a novel small molecule that activates TNFR1 by increasing inter-monomeric spacing in a ligand-independent manner. This shows that the conformational rearrangement of pre-ligand assembled receptor dimers can determine the activity of the receptor. By probing the interaction between the receptor and its downstream signaling molecule (TRADD) our findings support a new model of TNFR1 activation in which varying conformational states of the receptor act as a molecular switch in determining receptor function.

Original languageEnglish (US)
JournalProtein Science
DOIs
StateAccepted/In press - Jan 1 2020

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Keywords

  • conformational states
  • FRET
  • high-throughput screening
  • small molecule activator
  • structural dynamics
  • TNFR1 signaling

PubMed: MeSH publication types

  • Journal Article

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