Home » Key Drug Discovery Articles » Structural basis for corepressor assembly by the orphan nuclear receptor TLX

Structural basis for corepressor assembly by the orphan nuclear receptor TLX

Significant statement

The orphan nuclear receptor TLX /NR2E1 serves as a central regulator of neural stem cell self-renewal in the adult brain via its transcriptional repression activity. Yet little is known about TLX structure and its mechanism of corepressor recruitment. In this paper, we present the crystal structures of TLX in complex with the transcriptional repressor Atrophin. Our structural and biochemical studies reveal an unexpected cofactor-binding site on TLX, which is formed by the autorepressed conformation of orphan nuclear receptor TLX. This binding site interacts with a conserved ALXXLXXY motif in Atrophin, disruption of which affects orphan nuclear receptor orphan nuclear receptor TLX repressive activity. Interestingly, the novel binding site and the autorepressed conformation are conserved in the repressor class of orphan nuclear receptors. Mutations of corresponding residues in other members of this class of receptors compromise their repressor activities. Together, our studies provide a rational template for drug design to treat TLX-related diseases, define an essential corepressor motif to orphan nuclear receptor TLX-mediated repression, and determine the functional relevance to the autorepressed conformation in orphan nuclear receptors.

Figure Legend: Superposition of TLX/Atrophin and SHP/EID1. The structures of the orphan nuclear receptor SHP (green) in complex with its corepressor EID1 (yellow) and the orphan nuclear receptor TLX (purple) in complex with its corepressor Atrophin (orange) reveal two unconventional modes of nuclear receptors to recruit their corepressors.  our studies support that an orphan nuclear receptor can possess the both binding modes of for   gene repression and use the same corepressors.

 

Structural basis for corepressor assembly by the orphan nuclear receptor TLX. Global Medical Discovery

 

 

 

 

 

 

 

 

 

 

 

Journal Reference

Zhi X1, Zhou XE2, He Y2, Searose-Xu K2, Zhang CL3, Tsai CC4, Melcher K2, Xu HE5.

Genes Dev. 2015;29(4):440-50.

1Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA; Autophagy Research Center, [email protected] [email protected]

2Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA;

3Department of Molecular Biology, University of Texas Southwestern Medical Center, Texas 75390, USA;

4Department of Cell Biology and Neuroscience, University of California at Riverside, Riverside, California 92521, USA;

5Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA; Van Andel Research Institute-Shanghai Institute of Materia Medica (VARI/SIMM) Center, Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. [email protected]

 

Abstract

The orphan nuclear receptor TLX regulates neural stem cell self-renewal in the adult brain and functions primarily as a transcription repressor through recruitment of Atrophin corepressors, which bind to TLX via a conserved peptide motif termed the Atro box. Here we report crystal structures of the human and insect TLX ligand-binding domain in complex with Atro box peptides. In these structures, TLX adopts an autorepressed conformation in which its helix H12 occupies the coactivator-binding groove. Unexpectedly, H12 in this autorepressed conformation forms a novel binding pocket with residues from helix H3 that accommodates a short helix formed by the conserved ALXXLXXY motif of the Atro box. Mutations that weaken the TLX-Atrophin interaction compromise the repressive activity of TLX, demonstrating that this interaction is required for Atrophin to confer repressor activity to TLX. Moreover, the autorepressed conformation is conserved in the repressor class of orphan nuclear receptors, and mutations of corresponding residues in other members of this class of receptors diminish their repressor activities. Together, our results establish the functional conservation of the autorepressed conformation and define a key sequence motif in the Atro box that is essential for TLX-mediated repression.

© 2015 Zhi et al.; Published by Cold Spring Harbor Laboratory Press.

Go To PubMed

 

Global Medical Discovery Company