2 DISTINCT DIMERIZATION INTERFACES DIFFERENTIALLY MODULATE TARGET GENE SPECIFICITY OF NUCLEAR HORMONE RECEPTORS

Several nuclear receptors including the all-trans retinoic acid recept or RAR, form heterodimers with the 9-cis retinoic acid receptor, RXR. RXR-RAR heterodimers shaw an impressive flexibility in DNA binding and can recognize palindromic, inverted palindromes and direct repeats of the core half-site sequence AGGTCA. Dimerization interfaces in the DN A-binding domains of RXR, RAR, and thyroid hormone receptor (TR) that promote selective binding to strictly spaced direct repeats have previ ously been identified, However, an additional dimerization domain is p resent within the ligand-binding domains (LBDs) of these receptors. He re we localize a transferable 40-amino acid region within the LBDs of RXR, RAR, TR, and chicken ovalbumin upstream promoter transcription fa ctor that is critical for determining identity in the heterodimeric in teraction and for high-affinity DNA binding. This region overlaps almo st perfectly with a helical segment in the RXR LED crystal structure t hat was recently demonstrated to be part of the dimer interface, Our d ata suggest a sequential pathway for nuclear receptor dimerization whe reby the LED dimerization interface initiates the formation of solutio n heterodimers that, in turn, acquire the capacity to bind to a number of differently organized repeats. Formation of a second dimer interfa ce within the DNA-binding domain (DBD) restricts receptors to direct r epeat targets. Accordingly, the combination of an obligatory (LED) and an optional (DBD) dimerization domain imparts a dynamic DNA-binding p otential to the heterodimerizing receptors that both increases the div ersity of the hormonal response as well as providing a restricted set of target sequences in direct repeat elements that ensures physiologic al specificity.