UNIQUE RESPONSE PATHWAYS ARE ESTABLISHED BY ALLOSTERIC INTERACTIONS AMONG NUCLEAR HORMONE RECEPTORS

Heterodimerization is a common paradigm among eukaryotic transcription factors. The 9-cis retinoic acid receptor (RXR) serves as a common he terodimerization partner for several nuclear receptors, including the thyroid hormone receptor (T(3)R) and retinoic acid receptor (RAR). Thi s raises the question as to whether these complexes possess dual hormo nal responsiveness. We devised a strategy to examine the transcription al properties of each receptor individually or when tethered to a hete rodimeric partner. We find that the intrinsic binding properties of RX R are masked in T(3)R-RXR and RAR-RXR heterodimers. In contrast, RXR i s active as a non-DNA-binding cofactor with the NGFI-B/Nurr1 orphan re ceptors. Heterodimerization of RXR with constitutively active NGFI-B/N urr1 creates a novel hormone-dependent complex. These findings suggest that allosteric interactions among heterodimers create complexes with unique properties. We suggest that allostery is a critical feature un derlying the generation of diversity in hormone response networks.