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

Author

Listed:
  • David M. Heery

    (Molecular Endocrinology Laboratory, Imperial Cancer Research Fund)

  • Eric Kalkhoven

    (Molecular Endocrinology Laboratory, Imperial Cancer Research Fund)

  • Susan Hoare

    (Molecular Endocrinology Laboratory, Imperial Cancer Research Fund)

  • Malcolm G. Parker

    (Molecular Endocrinology Laboratory, Imperial Cancer Research Fund)

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.

Suggested Citation

  • David M. Heery & Eric Kalkhoven & Susan Hoare & Malcolm G. Parker, 1997. "A signature motif in transcriptional co-activators mediates binding to nuclear receptors," Nature, Nature, vol. 387(6634), pages 733-736, June.
    • Handle: RePEc:nat:nature:v:387:y:1997:i:6634:d:10.1038_42750
    DOI: 10.1038/42750
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    Cited by:

    1. Xiao-Jun Xie & Fu-Ning Hsu & Xinsheng Gao & Wu Xu & Jian-Quan Ni & Yue Xing & Liying Huang & Hao-Ching Hsiao & Haiyan Zheng & Chenguang Wang & Yani Zheng & Alus M Xiaoli & Fajun Yang & Sarah E Bondos , 2015. "CDK8-Cyclin C Mediates Nutritional Regulation of Developmental Transitions through the Ecdysone Receptor in Drosophila," PLOS Biology, Public Library of Science, vol. 13(7), pages 1-35, July.
    2. Efren Garcia-Maldonado & Andrew D. Huber & Sergio C. Chai & Stanley Nithianantham & Yongtao Li & Jing Wu & Shyaron Poudel & Darcie J. Miller & Jayaraman Seetharaman & Taosheng Chen, 2024. "Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Ramachandran Prakasam & Angela Bonadiman & Roberta Andreotti & Emanuela Zuccaro & Davide Dalfovo & Caterina Marchioretti & Debasmita Tripathy & Gianluca Petris & Eric N. Anderson & Alice Migazzi & Lau, 2023. "LSD1/PRMT6-targeting gene therapy to attenuate androgen receptor toxic gain-of-function ameliorates spinobulbar muscular atrophy phenotypes in flies and mice," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    4. Lunying Wu & Xiaohui Jing & Baolan Zhang & Shoujun Chen & Ran Xu & Penggen Duan & Danni Zou & Shengjian Huang & Tingbo Zhou & Chengcai An & Yuehua Luo & Yunhai Li, 2022. "A natural allele of OsMS1 responds to temperature changes and confers thermosensitive genic male sterility," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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