DETERMINANTS OF COACTIVATOR LXXLL MOTIF SPECIFICITY IN NUCLEAR RECEPTOR TRANSCRIPTIONAL ACTIVATION

Ligand-dependent activation of gene transcription by nuclear receptors is dependent on the recruitment of coactivators, including a family o f related NCoA/SRC factors, via a region containing three helical doma ins 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, diff erent combinations of two, appropriately spaced, LXDs are required for actions of the thyroid hormone, retinoic acid, peroxisome proliferato r-activated, or progesterone receptors. The specificity of LXD usage i n the cell appears to be dictated, at least in part, by specific amino acids carboxy-terminal to the core LXXLL motif that may make differen tial contacts with helices 1 and 3 (or 3') in receptor ligand-binding domains. Intriguingly, distinct carboxy-terminal amino acids are requi red for PPAR gamma activation in response to different ligands. Relate d LXXLL-containing motifs in NCoA-1/SRC-1 are also required for a func tional interaction with CBP, potentially interacting with a hydrophobi c binding pocket. Together, these data suggest that the LXXLL-containi ng motifs have evolved to serve overlapping roles that are likely to p ermit both receptor-specific and ligand-specific assembly of a coactiv ator complex, and that these recognition motifs underlie the recruitme nt of coactivator complexes required for nuclear receptor function.