Determinants of coactivator LXXLL motif specificity in nuclear receptor transcriptional activation

• Published in: Genes & development Vol. 12; no. 21; pp. 3357 - 3368
• Main Authors: McInerney, E M, Rose, D W, Flynn, S E, Westin, S, Mullen, T M, Krones, A, Inostroza, J, Torchia, J, Nolte, R T, Assa-Munt, N, Milburn, M V, Glass, C K, Rosenfeld, M G
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.11.1998
• Subjects: Amino Acid Sequence; Animals; Cells, Cultured; Fibroblasts - cytology; Gene Expression Regulation; Histone Acetyltransferases; Models, Molecular; Molecular Sequence Data; Nuclear Proteins - physiology; Nuclear Receptor Coactivator 1; Peptide Fragments - chemistry; Peptide Fragments - genetics; Peptide Fragments - physiology; Protein Structure, Secondary; Rats; Receptors, Cytoplasmic and Nuclear - chemistry; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Steroid - chemistry; Receptors, Steroid - genetics; Research Paper; Sequence Alignment; Trans-Activators - physiology; Transcription Factors - chemistry; Transcription Factors - genetics; Transcriptional Activation - physiology
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.12.21.3357

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 PPARgamma 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.