RAR and Rxr Dna Binding Domains

The DNA binding domains (DBDs) of members of the NR family are, in general, highly conserved, displaying approximately 60% identity at the amino acid level across the en-

Orphan Receptors

Chicken ovalbumin upstream promoter-transcription factors (COUP-TFI,II, III) Hepatic nuclear factor-4 (HNF-4) NGFI-B and related proteins

Receptor function

H2N-

H2N-

.COOH

.COOH

DNA binding Ligand binding Dimerization

Ligand-dependent transcriptional activation function core (AF2) Nuclear localization signal Ligand-independent transcriptional activation function (AF1) Silencing function

Figure 7.20. Nuclear receptor domain structure.

tire family. The DBD of both RARs and RXRs, and of all NRs, is composed of approximately 66-80 amino acids that are organized into two C2C2 zinc finger motifs (see Figs. 7.16 and 7.17), each of which tetrahedrally coordinates one zinc ion (134, 136). These two zinc fingers fold into a single structural motif comprised of two a helices, the recognition and support helices that are located on the knuckle on the carboxyl side of each zinc finger (134, 136). The two a-helices play very different roles in the function of the receptors: the recognition helii sits in the major groove of DNA and makes specific contacts with discriminating nucleotides within the response element; the support helix is oriented perpendicularly to the recognition helix and does not contact DNA at all (134,136). Rather, the support helii makes specific protein-protein contacts with and effectively buttresses the recognition helix into the major groove. This concept is illustrated schematically in Fig. 7.21. Biochemical (137,138) and crystallographic (134, 136) studies have revealed that three amino acids within the recognition helix are crucial for response element discrimination by most NRs.

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