Nuclear receptor structure/function

Tenbaum S,Baniahmad A. 1997. Nuclear receptors structure, function and involvement in disease. Int. J. Biochem. Cell Biol. 29 1325 11... 

Bain DL, et al. Nuclear receptor structure implications for function. Annu. Rev. Physiol. 2006. 

He, B., Gampe, R.T., Kole, A.J., Hnat, A.T., Stanley, T.B., An, G., Stewart, E.L., Kalman, R.I., Minges, J.T. and Wilson, E.M. (2004) Structural basis for androgen receptor interdomain and coactivator interactions suggests a transition in nuclear receptor activation function dominance. Molecular Cell, 16, 425—438. 

Peroxisome Proliferator-Activated Receptors. Figure 1 Common structural and functional features of nuclear receptor transcription factors. Consistent with other members of the nuclear receptor superfamily, the PPARs have a modular domain structure consisting of domains A/B, C, D, and E. Each domain is associated with specific functions. 

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]. 

In comparison to signaling pathways which utilize transmembrane receptors (see chapter 5, 8,11), signahng via nuclear receptors is of relatively simple structure. The pathways lead directly, with only a few participating protein components, from the extracellular space to the level of the DNA in the nucleus. Most important protein components of the signal pathway are known and well characterized. Nevertheless, we understand very little of the mechanism by which the activated receptors lead to a transcription initiation. This is due to the extreme complexity of transcription initiation in eucaryotes (see 1.2). Both the variety of proteins involved in the formation of a competent initiation complex, as well as the influence of chromatin structure, make it difficult to elucidate the exact function of nuclear receptors in transcription initiation. 

Extensive deletion and mutation studies, as well as sequence comparisons, have shown that the nuclear receptors are constructed modularly. At the level of the primary structure the steroid hormone receptors can be divided into five different domains (fig. 4.5), each with specific functions. 

Fig. 4.5. Domain structure of the nuclear receptors. Functional domains of nucear receptors are portrayed in a one dimensional, linear fashion.

The Ugand binding domain (section E in fig. 4.5) of the nuclear receptors harbors several functions. Apart from the specific binding site for the hormone, one finds further structural elements in this domain which mediates dimerization of the receptors as well as structural elements important for the ligand-mediated transactivation. 

Figure 17.3 The nuclear receptor superfamily. Steroid receptor family members and thyroid receptor family members differ in several structural and functional properties. The estrogen receptors share properties with both steroid and thyroid receptor families and are likely an evolutionary precursor to both families.

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