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A signature motif in transcriptional co-activators mediates binding to nuclear receptors

Nature volume 387, pages 733–736 (1997)Cite this article

Abstract

The binding of lipophilic hormones, retinoids and vitamins to members of the nuclear-receptor superfamily modifies the DNA-binding and transcriptional properties of these receptors, resulting in the activation or repression of target genes1,2. Ligand binding induces conformational changes in nuclear receptors and promotes their association with a diverse group of nuclear proteins, including SRC-1/p160 (3-5), TIF-2/GRIP-1 (refs 6, 7) and CBP/p300 (refs 4, 5, 8, 9) which function as co-activators of transcription, and RIP-140 (ref. 10), TIF-1 (ref. 11) and TRIP-1/SUG-1 (refs 12, 13) whose functions are unclear. Here we report that a short sequence motif LXXLL (where L is leucine and X is any amino acid) present in RIP-140, SRC-1 and CBP is necessary and sufficient to mediate the binding of these proteins to liganded nuclear receptors. We show that the ability of SRC-1 to bind the oestrogen receptor and enhance its transcriptional activity is dependent upon the integrity of the LXXLL motifs and on key hydrophobic residues in a conserved helix (helix 12) of the oestrogen receptor that are required for its ligand-induced activation function14. We propose that the LXXLL motif is a signature sequence that facilitates the interaction of different proteins with nuclear receptors, and is thus a defining feature of a new family of nuclear proteins.

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Figure 1: Interaction of LXXLL motifs derived from co-activators with the ER.
Figure 2: The LXXLL sequence is a signature motif in proteins that bind the LBDs of nuclear receptors.
Figure 3: LXXLL motifs are required for binding of SRC-1 to the ER LBD in vitro and for the ability of SRC-1 to enhance ER activity in vivo.

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Acknowledgements

We thank our colleagues for discussion and for communicating unpublished results; P. Freemont, N. Jones and A. Parker for their suggestions and for critically reading the manuscript; P. Chambon for pBL1, pASV3 and the anti-ER monoclonal antibody; B. Katzenellenbogen for 2EREppS2-CAT; N. Jones for the yeast strain; K. Hobbs for oligonucleotides; N. O'Reilly for peptides; W. Bessant for photography; and G. Clark for automated sequencing. D.M.H. and E.K. were supported by grants from the European Community TMR program and the Netherlands Organisation of Scientific Research (NWO), respectively.

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  1. Molecular Endocrinology Laboratory, Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, WC2A 3PX, London, UK

    David M. Heery, Eric Kalkhoven, Susan Hoare & Malcolm G. Parker

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Correspondence to Malcolm G. Parker.

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Heery, D., Kalkhoven, E., Hoare, S. et al. A signature motif in transcriptional co-activators mediates binding to nuclear receptors. Nature 387, 733–736 (1997). https://doi.org/10.1038/42750

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