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J. Biol. Chem., Vol. 280, Issue 7, 5682-5692, February 18, 2005

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Biochemical and NMR Mapping of the Interface between CREB-binding Protein and Ligand Binding Domains of Nuclear Receptor

BEYOND THE LXXLL MOTIF^*

Fabrice A. C. Klein, R. Andrew Atkinson, Noelle Potier¶, Dino Moras, and Jean Cavarelli||

From the Département de Biologie et Génomique Structurales, UMR 7104, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP Strasbourg, 1 rue Laurent Fries Illkirch 67404, and the ^¶Laboratoire de Spectrométrie de Masse Bio-Organique, CNRS UMR 7509, Ecole Européenne de Chimie, Polymères et Matériaux, 25 rue Becquerel, Strasbourg 67087 cedex, France

CBP, cAMP-response element-binding protein (CREB)-binding protein, plays an important role as a general cointegrator of various signaling pathways and interacts with a large number of transcription factors. Interactions of CBP with ligand binding domains (LBDs) of nuclear receptors are mediated by LXXLL motifs, as are those of p160 proteins, although the number, distribution, and precise sequences of the motifs differ. We used a large N-terminal fragment of murine CBP to map by biochemical methods and NMR spectroscopy the interaction domain of CBP with the LBDs of several nuclear receptors. We show that distinct zones of that fragment are involved in the interactions: a 20-residue segment containing the LXXLL motif (residues 61–80) is implicated in the interaction with all three domains tested (peroxisome proliferator-activated receptor -LBD, retinoid X receptor -LBD, and estrogen-related receptor -LBD), whereas a second N-terminal well conserved block of around 25 residues centered on a consensus L⁴⁰PDEL⁴⁴ motif constitutes a secondary motif of interaction with peroxisome proliferator-activated receptor -LBD. Sequence analysis reveals that both zones are well conserved in all vertebrate p300/CBP proteins, suggesting their functional importance. Interactions of p300/CBP coactivators with the LBDs of nuclear receptors are not limited to the canonical LXXLL motifs, involving both a longer contiguous segment around the motif and, for certain domains, an additional zone.

Received for publication, October 14, 2004 , and in revised form, November 10, 2004.

^* This work was supported by the CNRS, INSERM, Université Louis Pasteur (Strasbourg), and by funds from the Genopôle Alsace-Lorraine and the European Commission as SPINE, Contract QLG2-CT-2002-00988 under the Public Research, Technology, and Development program Quality of Life and Management of Living Resources. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Département de Pathologie Moléculaire, Illkirch UMR7104, France.

^|| To whom correspondence should be addressed. Tel.: 33-03-8865-3256; Fax: 33-03-8865-3276; E-mail: cava{at}igbmc.u-strasbg.fr.

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