Atypical Nuclear Receptors

Several structurally divergent members of the NR superfamily have been isolated. The human gene DAX-1, which lacks a conventional zinc finger DBD, encodes one of these atypical NRs. DAX-1 contains a region consisting of four repeats of alanine and glycine-rich sequences that likely binds DNA. It is responsible for dosage-sensitive sex- and X-linked adrenal hypoplasia, an inherited disorder of adrenal gland development.68 The LBD of DAX-1 is similar to typical members of the NR superfamily.

The heterodimeric partner of DAX-1, SHP (short heterodimer partner), is structurally sim-ilar,69 containing a putative LBD but lacking a conventional DBD. Also, SHP has been pro posed to function as a negative regulator of NR signaling pathways because it interacts with and inhibits the transcriptional activity of various nonsteroid receptors, including TRs, RARs, and agonist-bound ERa and ERjS. This inhibition is caused in part by SHP-associated repression activity and by competition with coactivators for receptor binding.70-72

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