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This version published online on September 8, 2005
Molecular Endocrinology, doi:10.1210/me.2005-0313
A more recent version of this article appeared on February 1, 2006
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Submitted on August 1, 2005
Accepted on September 1, 2005

A Single Nucleotide in an Estrogen Related Receptor {alpha} Site Can Dictate Mode of Binding and PGC-1{alpha} Activation of Target Promoters

Janelle B. Barry, Josée Laganière, and Vincent Giguère*

Molecular Oncology Group, McGill University Health Centre and Departments of Biochemistry, Medicine and Oncology, McGill University, Montréal, Québec, Canada H3A 1A1

* To whom correspondence should be addressed. E-mail: vincent.giguere{at}mcgill.ca.

The orphan nuclear receptor estrogen related receptor {alpha} (ERR{alpha}, NR3B1) is a constitutively active transcription factor that controls multiple processes, most notably mitochondrial function. ERR{alpha} preferentially binds to a nine nucleotide extended half-site sequence TNAAGGTCA, referred to as the ERRE, as either a monomer or a dimer, although how the mode of DNA binding is dictated remains to be determined. Here, we used variants of the extended half-site sequence and selective DNA binding domain mutants of ERR{alpha} to investigate the effects of ERRE sequence specificity on ERR{alpha} DNA binding mode, transactivation and interaction with the coactivator protein PGC-1{alpha}. We found that the base at the N position of the TNAAGGTCA sequence dictated ERR{alpha} binding preference as a monomer or dimer. In addition, we demonstrated that the threonine residue at position 124 (Thr124) was a determinant of ERR{alpha} DNA-dependent dimerization. Transfection experiments also indicated that substituting a thymidine for a cytosine at the N position in the ERRE of the native ERR{alpha} target promoter TFF1 considerably diminished the transcriptional response of the ERR{alpha}/PGC-1{alpha} complex. These results suggest that a single nucleotide in an ERR{alpha} binding site can determine specific configuration to the receptor and productive interaction with the coactivator PGC-1{alpha}.
Key words: Nuclear receptors • transcription • dimerization • DNA binding

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERRα
Coregulators:   PGC-1



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