Nucleic Acids Research, Vol 24, Issue 18 3490-3498, Copyright © 1996 by Oxford University Press
M Downes, LJ Burke and GE Muscat
Rev-erbA alpha is an orphan nuclear receptor that functions as a dominant
transcriptional repressor. Tissue culture and in situ hybridisation studies
indicated that Rev-erbA alpha plays an important role in mammalian
differentiation and development. Previous studies have localised the
silencing domain of Rev-erbA alpha to the D/E region of the orphan
receptor. This study utilised the GAL4 hybrid system to demonstrate that
efficient repression is mediated by 34 amino acids (aa) between aa 455 and
488 in the E region of the receptor. This domain contains the ligand
binding domain (LBD)-signature motif [(F/W)AKxxxxFxxLxxxDQxxLL] and a
region that, according to the recently published crystal structures of
steroid receptors, would be predicted to form helix 5 of the canonical LBD
structure. Fine deletions and site- specific mutagenesis indicated that
both the LBD signature motif and helix 5 were necessary for efficient
silencing. Utilising mammalian two hybrid technology, we have also
demonstrated that Rev-erbA alpha does not associate with the interaction
domain (aa 2218-2451) of the nuclear receptor corepressor, N-CoR, that is
known to interact with the thyroid hormone and retinoic acid receptors.
This suggested that transcriptional repression by Rev-erbA alpha is not
mediated through an interaction with N-CoR. In conclusion, we have
identified and characterised the minimal domain of Rev-erbA alpha, that
mediates transcriptional repression by this orphan receptor.
ARTICLES
Transcriptional repression by Rev-erbA alpha is dependent on the signature motif and helix 5 in the ligand binding domain: silencing does not involve an interaction with N-CoR
University of Queensland, Centre for Molecular and Cellular Biology, Ritchie Research Laboratories, St Lucia, Australia.
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