Differential orientations of the DNA-binding domain and carboxy-terminal dimerization interface regulate binding site selection by nuclear receptor heterodimers.
Retinoic acid, thyroid hormone, and vitamin D receptors preferentially activate target genes through response elements that consist of direct repeat arrangements of a core recognition motif of consensus sequence AGGTCA. We present evidence that the preference for direct repeat elements arises from two fundamental differences from steroid hormone receptors. First, retinoic acid, thyroid hormone, and vitamin D receptors are demonstrated to preferentially form heterodimers with the retinoid X receptors. These interactions are mediated by the carboxy-terminal dimerization interface, with heterodimer preference specified by actions of the DNA-binding domain. Second, the DNA-binding domains of heterodimeric receptors appear to be rotationally flexible with respect to the carboxy-terminal dimerization interface. Several independent lines of evidence suggest that, relative to the retinoid X and steroid hormone receptors, the DNA-binding domain of the thyroid hormone receptor is preferentially rotated by approximately 180 degrees with respect to its carboxy-terminal dimerization interface. As a result, solution interactions between the carboxy-terminal dimerization interfaces of the retinoid X and thyroid hormone receptors are predicted to lead to the preferential alignment of their respective DNA-binding domains in a direct repeat configuration. This alignment would position the retinoid X receptor over the upstream recognition motif of direct repeat response elements. Differential orientations of the DNA-binding domain, which contribute to the polarity of heterodimer binding, are regulated by a short sequence (the A box) that is located between the conserved DNA-binding and carboxy-terminal dimerization domains.
Division of Cellular and Molecular Medicine, University of California, San Diego, La Jolla 92093-0656.
R
R
Kurokawa
V C
VC
Yu
A
A
Näär
S
S
Kyakumoto
Z
Z
Han
S
S
Silverman
M G
MG
Rosenfeld
C K
CK
Glass
D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D002117:Calcitriol / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D012091:Repetitive Sequences, Nucleic Acid
D002352:Carrier Proteins; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D004247:DNA; D002117:Calcitriol