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Plasticity of the Ecdysone Receptor DNA Binding Domain

Marek Orowski, Monika Szyszka, Agnieszka Kowalska, Iwona Grad, Anna Zoglowek, Grzegorz Rymarczyk, Piotr Dobryszycki, Daniel Krowarsch, Fraydoon Rastinejad, Marian Kochman and Andrzej Oyhar

Institute of Organic Chemistry, Biochemistry and Biotechnology (M.O., M.S., A.K., I.G., A.Z., G.R., P.D., M.K., A.O.), Division of Biochemistry, Wrocaw University of Technology, 50-370 Wrocaw, Poland; Laboratory of Protein Engineering (D.K.), Institute of Biochemistry and Molecular Biology, University of Wrocaw, 50-137 Wrocaw, Poland; and Department of Pharmacology (F.R.), Department of Molecular Genetics and Biochemistry, University of Virginia Health System, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Andrzej Oyhar, Institute of Organic Chemistry, Biochemistry and Biotechnology, Division of Biochemistry, Wrocaw University of Technology, Wybrzee Wyspiaskiego 27, 50–370 Wrocaw, Poland. E-mail: andrzej.ozyhar{at}pwr.wroc.pl.

Ecdysteroids coordinate molting and metamorphosis in insects via a heterodimer of two nuclear receptors, the ecdysone receptor (EcR) and the ultraspiracle (Usp) protein. Here we show how the DNA-recognition -helix and the T box region of the EcR DNA-binding domain (EcRDBD) contribute to the specific interaction with the natural response element and to the stabilization of the EcRDBD molecule. The data indicate a remarkable mutational tolerance with respect to the DNAbinding function of the EcRDBD. This is particularly manifested in the heterocomplexes formed between the EcRDBD mutants and the wild-type Usp DNA-binding domain (UspDBD). Circular dichroism (CD) spectra and protein unfolding experiments indicate that, in contrast to the UspDBD, the EcRDBD is characterized by a lower -helix content and a lower stability. As such, the EcRDBD appears to be an intrinsically unstructured protein-like molecule with a high degree of intramolecular plasticity. Because recently published crystal structures indicate that the ligand binding domain of the EcR is also characterized by the extreme adaptability, we suggest that plasticity of the EcR domains may be a key factor that allows a single EcR molecule to mediate diverse biological effects.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRβ  |  EcR  |  FXRβ  |  VDR  |  RXRα  |  usp

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