Selective LXXLL peptides antagonize transcriptional activation by the retinoid-related orphan receptor RORgamma.

Abstract:

:The retinoid-related orphan receptor gamma (RORgamma) has been shown to function as a positive regulator of transcription in many cell lines. Transcriptional activation by nuclear receptors involves recruitment of co-activators that interact with receptors through their LXXLL motifs (NR box). In this study, we analyze the interaction of RORgamma with the co-activator SRC1 and use a series of LXXLL-containing peptides to probe for changes in the conformation of the co-activator interaction surface of the RORgamma LBD. We demonstrate that the H3-4/H12 co-activator interaction surface of RORgamma displays a selectivity for LXXLL peptides that is distinct from those of other nuclear receptors. LXXLL peptides that interacted with RORgamma efficiently antagonized RORgamma-mediated transcriptional activation. Mutations E502Q and Y500F in H12, and K334A, Q347A, and I348D in H3 and H4 of RORgamma, severely impact the recruitment of LXXLL peptides. The effects of these mutations are consistent with predictions made on the basis of the structure of the RORgamma(LBD) derived through homology modeling. These peptide antagonists provide a useful tool to analyze the conformation changes in the RORgamma(LBD) and to study RORgamma receptor signaling.

authors

Kurebayashi S,Nakajima T,Kim SC,Chang CY,McDonnell DP,Renaud JP,Jetten AM

doi

10.1016/j.bbrc.2004.01.131

subject

Has Abstract

pub_date

2004-03-19 00:00:00

pages

919-27

issue

4

eissn

0006-291X

issn

1090-2104

pii

S0006291X04001779

journal_volume

315

pub_type

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