Determinants of coactivator LXXLL motif specificity in nuclear receptor transcriptional activation (original) (raw)

  1. Eileen M. McInerney1,6,
  2. David W. Rose3,6,
  3. Sarah E. Flynn1,
  4. Stefan Westin2,
  5. Tina-Marie Mullen1,3,
  6. Anna Krones1,
  7. Juan Inostroza1,
  8. Joseph Torchia1,7,
  9. Robert T. Nolte5,
  10. Nuria Assa-Munt4,
  11. Michael V. Milburn5,
  12. Christopher K. Glass1,2,3, and
  13. Michael G. Rosenfeld1,8
  14. 1Howard Hughes Medical Institute, 2Division of Cellular and Molecular Medicine, and 3Whittier Diabetes Program, Department and School of Medicine, University of California at San Diego, La Jolla, California 92093-0648 USA; 4The Burnham Institute, La Jolla, California 92037 USA; 5GlaxcoWellcome Inc., Division of Chemistry, Department of Structural Chemistry, and Department of Medicinal Chemistry, Research Triangle Park, North Carolina 27709 USA

Abstract

Ligand-dependent activation of gene transcription by nuclear receptors is dependent on the recruitment of coactivators, including a family of related NCoA/SRC factors, via a region containing three helical domains sharing an LXXLL core consensus sequence, referred to as LXDs. In this manuscript, we report receptor-specific differential utilization of LXXLL-containing motifs of the NCoA-1/SRC-1 coactivator. Whereas a single LXD is sufficient for activation by the estrogen receptor, different combinations of two, appropriately spaced, LXDs are required for actions of the thyroid hormone, retinoic acid, peroxisome proliferator-activated, or progesterone receptors. The specificity of LXD usage in the cell appears to be dictated, at least in part, by specific amino acids carboxy-terminal to the core LXXLL motif that may make differential contacts with helices 1 and 3 (or 3′) in receptor ligand-binding domains. Intriguingly, distinct carboxy-terminal amino acids are required for PPARγ activation in response to different ligands. Related LXXLL-containing motifs in NCoA-1/SRC-1 are also required for a functional interaction with CBP, potentially interacting with a hydrophobic binding pocket. Together, these data suggest that the LXXLL-containing motifs have evolved to serve overlapping roles that are likely to permit both receptor-specific and ligand-specific assembly of a coactivator complex, and that these recognition motifs underlie the recruitment of coactivator complexes required for nuclear receptor function.

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