TY - JOUR
T1 - Mutations in retinoid X receptor that impair heterodimerization with specific nuclear hormone receptor
AU - Lee, Soo Kyung
AU - Lee, Bora
AU - Lee, Jae Woon
PY - 2000/10/27
Y1 - 2000/10/27
N2 - Retinoid X receptor (RXR) serves as a promiscuous heterodimerization partner for many nuclear receptors through the identity box, a 40-amino acid subregion within the ligand binding domain. In this study, we randomly mutated two specific residues within the human RXRα identity box region previously identified as important determinants in heterodimerization (i.e. Ala416 and Arg421). Interestingly, most of these mutants still retained wild type interactions with thyroid hormone receptor (TR), retinoic acid receptor, peroxisome proliferator-activated receptor α, small heterodimer partner, and constitutive androstane receptor. However, RXR-A416D and R421L were specifically impaired for interactions with TR, whereas RXR-A416K lost both TR and retinoic acid receptor interactions. Accordingly, RXR-A416D did not support T3 transactivation in mammalian cells, whereas RXR-A416K was not supportive of transactivation by retinoids or T3. These results provide a basis upon which to further design mutant RXRs highly selective in heterodimerization, potentially useful tools to probe nuclear receptor function in vivo.
AB - Retinoid X receptor (RXR) serves as a promiscuous heterodimerization partner for many nuclear receptors through the identity box, a 40-amino acid subregion within the ligand binding domain. In this study, we randomly mutated two specific residues within the human RXRα identity box region previously identified as important determinants in heterodimerization (i.e. Ala416 and Arg421). Interestingly, most of these mutants still retained wild type interactions with thyroid hormone receptor (TR), retinoic acid receptor, peroxisome proliferator-activated receptor α, small heterodimer partner, and constitutive androstane receptor. However, RXR-A416D and R421L were specifically impaired for interactions with TR, whereas RXR-A416K lost both TR and retinoic acid receptor interactions. Accordingly, RXR-A416D did not support T3 transactivation in mammalian cells, whereas RXR-A416K was not supportive of transactivation by retinoids or T3. These results provide a basis upon which to further design mutant RXRs highly selective in heterodimerization, potentially useful tools to probe nuclear receptor function in vivo.
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U2 - 10.1074/jbc.M006418200
DO - 10.1074/jbc.M006418200
M3 - Article
C2 - 10948200
AN - SCOPUS:0034721838
SN - 0021-9258
VL - 275
SP - 33522
EP - 33526
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 43
ER -