Conformational states of TNFR1 as a molecular switch for receptor function

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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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)
Pages (from-to)1401-1415
Number of pages15
JournalProtein Science
Volume29
Issue number6
DOIs
StatePublished - Jun 1 2020

Bibliographical note

Funding Information:
We thank Colin Lim and Zhipeng Ding from the Sachs group, and Samantha Yuen from the Thomas group for technical support. Flow cytometry was performed at the UMN Lillehei Heart Institute, spectroscopy at the UMN Biophysical Technology Center and compound dispensing and surface plasmon resonance (S10 Shared Instrument Grant 1S10OD021539‐01 funded by the Office of Research Infrastructure Programs (ORIP)/National Institutes of Health (NIH)) at the UMN Institute of Therapeutic Drug Discovery and Development (ITDD) High‐Throughput Screening Laboratory.

Funding Information:
National Institutes of Health, Grant/Award Numbers: R01GM107175, R35GM131814; University of Minnesota, Grant/Award Number: Doctoral Dissertation Fellowship; Office of Research Infrastructure Programs, Grant/Award Number: 1S10OD021539‐01 Funding information

Funding Information:
We thank Colin Lim and Zhipeng Ding from the Sachs group, and Samantha Yuen from the Thomas group for technical support. Flow cytometry was performed at the UMN Lillehei Heart Institute, spectroscopy at the UMN Biophysical Technology Center and compound dispensing and surface plasmon resonance (S10 Shared Instrument Grant 1S10OD021539-01 funded by the Office of Research Infrastructure Programs (ORIP)/National Institutes of Health (NIH)) at the UMN Institute of Therapeutic Drug Discovery and Development (ITDD) High-Throughput Screening Laboratory.

Keywords

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

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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