Molecular determinants of nuclear receptor-corepressor interaction.
Retinoic acid and thyroid hormone receptors can act alternatively as ligand-independent repressors or ligand-dependent activators, based on an exchange of N-CoR or SMRT-containing corepressor complexes for coactivator complexes in response to ligands. We provide evidence that the molecular basis of N-CoR recruitment is similar to that of coactivator recruitment, involving cooperative binding of two helical interaction motifs within the N-CoR carboxyl terminus to both subunits of a RAR-RXR heterodimer. The N-CoR and SMRT nuclear receptor interaction motifs exhibit a consensus sequence of LXX I/H I XXX I/L, representing an extended helix compared to the coactivator LXXLL helix, which is able to interact with specific residues in the same receptor pocket required for coactivator binding. We propose a model in which discrimination of the different lengths of the coactivator and corepressor interaction helices by the nuclear receptor AF2 motif provides the molecular basis for the exchange of coactivators for corepressors, with ligand-dependent formation of the charge clamp that stabilizes LXXLL binding sterically inhibiting interaction of the extended corepressor helix.
Perissi
V
V
University of California, San Diego (UCSD), Graduate Student, Molecular Pathology Program, UCSD, La Jolla, California 92095-0648 USA.
Staszewski
L M
LM
McInerney
E M
EM
Kurokawa
R
R
Krones
A
A
Rose
D W
DW
Lambert
M H
MH
Milburn
M V
MV
Glass
C K
CK
Rosenfeld
M G
MG
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D016384:Consensus Sequence; D017124:Conserved Sequence; D019281:Dimerization; D006367:HeLa Cells; D006801:Humans; D046911:Macromolecular Substances; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D017433:Protein Structure, Secondary; D051381:Rats; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D047488:Retinoid X Receptors; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism
D046911:Macromolecular Substances; C539127:NCOR1 protein, human; C539129:Ncor1 protein, rat; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D011994:Recombinant Proteins; D012097:Repressor Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors