Regulation of retinoid signalling by receptor polarity and allosteric control of ligand binding.
Retinoic acid receptors (RARs) and retinoid X receptors (RXRs) regulate transcription by binding to response elements in target genes that generally consist of two direct repeat half-sites of consensus sequence AGGTCA (ref. 1). RAR/RXR heterodimers activate transcription in response to all-trans or 9-cis retinoic acid by binding to direct repeats spaced by five base pairs (DR5 elements), such that RAR occupies the downstream half-site. RXR homodimers activate transcription in response to 9-cis retinoic acid by binding to direct repeats spaced by one base pair (DR1 elements). Although RXR/RAR heterodimers bind to DR1 elements with higher affinity than RXR homodimers, in most contexts they are unable to activate transcription in response to either all-trans or 9-cis retinoic acid. As a result, RARs inhibit RXR-dependent transcription from these sites. We report that the switching of the RAR from an activator to an inhibitor of retinoid-dependent transcription requires that it be bound to the upstream half-site of DR1 elements and that it allosterically block the binding of ligand to the RXR.
Kurokawa
R
R
Division of Cellular and Molecular Medicine, University of California, San Diego 92093-0656.
DiRenzo
J
J
Boehm
M
M
Sugarman
J
J
Gloss
B
B
Rosenfeld
M G
MG
Heyman
R A
RA
Glass
C K
CK
D000494:Allosteric Regulation; D001483:Base Sequence; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004926:Escherichia coli; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid; D047488:Retinoid X Receptors; D015398:Signal Transduction; D014157:Transcription Factors; D014158:Transcription, Genetic
D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D004247:DNA