Conformation of the Mineralocorticoid Receptor N-terminal Domain: Evidence for Induced and Stable Structure

Fischer, K., Kelly, S.M. , Watt, K., Price, N.C. and McEwan, I. J. (2010) Conformation of the Mineralocorticoid Receptor N-terminal Domain: Evidence for Induced and Stable Structure. Molecular Endocrinology, 24(10), pp. 1935-1948. (doi:10.1210/me.2010-0005)

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Publisher's URL: http://dx.doi.org/10.1210/me.2010-0005

Abstract

The mineralocorticoid receptor (MR) binds the steroid hormones aldosterone and cortisol and has an important physiological role in the control of salt homeostasis. Regions of the protein important for gene regulation have been mapped to the amino-terminal domain (NTD) and termed activation function (AF)1a, AF1b, and middle domain (MD). In the present study, we used a combination of biophysical and biochemical techniques to investigate the folding and function of the MR-NTD transactivation functions. We demonstrate that MR-AF1a and MR-MD have relatively little stable secondary structure but have the propensity to form {alpha}-helical conformation. Induced folding of the MR-MD enhanced protein-protein binding with a number of coregulatory proteins, including the coactivator cAMP response element-binding protein-binding protein and the corepressors SMRT and RIP140. By contrast, the MR-AF1b domain appeared to have a more stable conformation consisting predominantly of {beta}-secondary structure. Furthermore, MR-AF1b specifically interacted with the TATA-binding protein, via an LxxLL-like motif, in the absence of induced folding. Together, these data suggest that the MR-NTD contains a complex transactivation system made up of distinct structural and functional domains. The results are discussed in the context of the induced folding paradigm for steroid receptor NTDs

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Price, Prof Nicholas and Kelly, Dr Sharon
Authors: Fischer, K., Kelly, S.M., Watt, K., Price, N.C., and McEwan, I. J.
College/School:College of Medical Veterinary and Life Sciences
Journal Name:Molecular Endocrinology
ISSN:0888-8809

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