LXXLL motifs, nuclear receptor

Nuclear receptors exert their different transcriptional functions through interactions with and the recruitment of co-factors to responsive promoters. Co-factors are either positive or negative regulatory proteins and are classified as co-activators, which promote, or co-repressors, which attenuate the activity of nuclear hormone receptors [46]. The molecular mechanisms that regulate the mutually exclusive interactions of the nuclear receptor with either class of co-factors have been analysed by crystallographic studies. Functional and structural studies have shown that co-activators interact with the transactivation function (AF) of nuclear hormone receptors via short, leucine-rich motifs (LXXLL) termed NR boxes , thereby transducing hormonal signals to the basal transcription machinery [47]. 

The Glaxo group tvas the first to report the structure of a heterodimeric complex between two activated NHRs (peroxisome proliferator-activated receptor-y) PPAR-y and (retinoid X receptor-a) RXR-a. The structure (PDB entry 1FM6) of this heterodimer complex contains six components the two receptor LBDs, their two respective ligands, and two peptides derived from the steroid receptor co-activator-1 (SRC-1). These peptides contain a conserved LxxLL motif that is present in this class of co-activators. The complex is butterfly shaped, with both LBDs adopting the conserved helical sandwich fold previously reported for other ligand-bound nuclear receptors. PPAR-y contains 13 a-helices and four short / -strands, while RXR-a is composed of 11 a-helices and two short yS-strands [3]. This complex is illustrated in Fig. 1.1. 

A series of proteins or protein complexes with coactivator function for nuclear receptors has been identified that specifically interact with the activated, liganded receptor. The most abundant ones are now included in the pl60 family of coactivators with the steroid receptor coactivator 1, SRC-1, as a well-characterized member. Another group of coactivators is present as multiprotein complexes like the TRAP complex (TRAP, thyroid hormone receptor activating protein). A common receptor interaction motif LXXLL is found on these coactivators which mediates at least part of the interaction with the AF2 domain of the receptor. 

Fowlkes, D. and McDonnell, D.P. (1999) Dissection of the LXXLL nuclear receptor— coactivator interaction motif using combinatorial peptide libraries discovery of peptide antagonists of estrogen receptors a and p. Molecular and Cellular Biology, 19, 8226-8239. 

Dubbink, H.J., Hersmus, R., Pike, A.C.W., Molier, M., Brinkmann, A.O., Jenster, G. and Trapman, J. (2006) Androgen receptor ligand-binding domain interaction and nuclear receptor specificity of FXXLF and LXXLL motifs as determined by L/F swapping. Molecular Endocrinology, 20, 1742-1755. 

Mclnerney, 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. and Rosenfeld, M.G. (1998) Determinants of coactivator LXXLL motif specificity in nuclear receptor transcriptional activation. Genes and Development, 12, 3357-3368. 

The pl60 family of coactivators including steroid receptor coactivator 1 (SRC-1), TIF/GRIP (SRC-2), and ACTR/pCIP (SRC-3) [24] stimulates the transcriptional activity of nuclear receptors. The pi60 family of coactivators has three LXXLL motifs in the receptor-interacting domain (RID) that interacts with the AF-2 domain of nuclear receptors. SRC-1 is a weak HAT that interacts with p300/CBP and recruits CARM-1. 

Similar to how the coactivators use the LXXLL motif as a docking point, the corepressors contain an LXXIIXXXL peptide referred to as the corepressor nuclear receptor (CoRNR) box [66]. The precise nature of the interaction between corepressors and NRs remained elusive before the solution of the crystal structure between PPARa and a peptide from SMRT. As mentioned briefly in a previous section, this structure shows that the CoRNR box occupies the same general site on PPARa as the coactivator LXXLL motif. However,... 

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