Orphan Nuclear Receptor NR4A1 Binds a Novel Protein Interaction Site on Anti-apoptotic B Cell Lymphoma Gene 2 Family Proteins.

Abstract

B cell lymphoma gene 2 (Bcl-2) family proteins are key regulators of programmed cell death and important targets for drug discovery. Pro-apoptotic and anti-apoptotic Bcl-2 family proteins reciprocally modulate their activities in large part through protein interactions involving a motif known as BH3 (Bcl-2 homology 3). Nur77 is an orphan member of the nuclear receptor family that lacks a BH3 domain but nevertheless binds certain anti-apoptotic Bcl-2 family proteins (Bcl-2, Bfl-1, and Bcl-B), modulating their effects on apoptosis and autophagy. We used a combination of NMR spectroscopy-based methods, mutagenesis, and functional studies to define the interaction site of a Nur77 peptide on anti-apoptotic Bcl-2 family proteins and reveal a novel interaction surface. Nur77 binds adjacent to the BH3 peptide-binding crevice, suggesting the possibility of cross-talk between these discrete binding sites. Mutagenesis of residues lining the identified interaction site on Bcl-B negated the interaction with Nur77 protein in cells and prevented Nur77-mediated modulation of apoptosis and autophagy. The findings establish a new protein interaction site with the potential to modulate the apoptosis and autophagy mechanisms governed by Bcl-2 family proteins.

• Authors: Paulo H C Godoi, Rachel P Wilkie-Grantham, Asami Hishiki, Renata Sano, Yasuko Matsuzawa, Hiroko Yanagi, Claudia E Munte, Ya Chen, Yong Yao, Francesca M Marassi, Hans R Kalbitzer, Shu-Ichi Matsuzawa, John C Reed
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 291 Issue 27 Pg. 14072-14084 (Jul 01 2016) ISSN: 1083-351X [Electronic] United States
• PMID: 27129202 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• NR4A1 protein, human
• Nuclear Receptor Subfamily 4, Group A, Member 1
• Proto-Oncogene Proteins c-bcl-2

Topics

• Humans
• Nuclear Receptor Subfamily 4, Group A, Member 1 (metabolism)
• Protein Binding
• Proto-Oncogene Proteins c-bcl-2 (chemistry, metabolism)