HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lind, U. Articles by Carlstedt-Duke, J. Search for Related Content PubMed PubMed Citation Articles by Lind, U. Articles by Carlstedt-Duke, J. Social Bookmarking                      What's this?

J Biol Chem, Vol. 274, Issue 26, 18515-18523, June 25, 1999

Valine 571 Functions as a Regional Organizer in Programming the Glucocorticoid Receptor for Differential Binding of Glucocorticoids and Mineralocorticoids

Ulrika Lind, Paulette Greenidge^¶, Jan-Åke Gustafsson, Anthony P. H. Wright^**, and Jan Carlstedt-Duke

From the  Department of Medical Nutrition, Karolinska Institutet, Huddinge Hospital, Novum, S-141 86, ^¶ Karo Bio AB, Novum, S-141 57, the  Department of Biosciences at Novum, Karolinska Institutet, S-141 57, and ^** Södertörns Högskola, Box 4101, S-141 04 Huddinge, Sweden

The glucocorticoid receptor (GR) interacts specifically with glucocorticoids, whereas its closest relative, the mineralocorticoid receptor (MR), interacts with both glucocorticoids and mineralocorticoids, such as aldosterone. To investigate the mechanism underlying the glucocorticoid/mineralocorticoid specificity of the GR, we used a yeast model system to screen for GR ligand-binding domain mutants, substituted with MR residues in the segment 565-574, that can be efficiently activated by aldosterone. In all such increased activity mutants, valine 571 was replaced by methionine, even though most mutants also contained substitutions of other residues with their MR counterparts. Further analysis in yeast and COS-7 cells has revealed that the identity of residue 571 determines the behavior of other MR substituted residues in the 565-574 segment. Generally, MR substitutions in this region are only consistent with aldosterone binding if residue 571 is also replaced with methionine (MR conformation). If residue 571 is valine (GR conformation), most other MR substitution mutants drastically reduce interaction with both mineralocorticoid and glucocorticoid hormones. Based on these functional data, we hypothesize that residue 571 functions as a regional organizer involved in discriminating between glucocorticoid and mineralocorticoid hormones. We have used a molecular model of the GR ligand-binding domain in an attempt to interpret our functional data in structural terms.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				F. M. Rogerson, Y.-Z. Yao, R. E. Elsass, N. Dimopoulos, B. J. Smith, and P. J. Fuller A Critical Region in the Mineralocorticoid Receptor for Aldosterone Binding and Activation by Cortisol: Evidence for a Common Mechanism Governing Ligand Binding Specificity in Steroid Hormone Receptors Mol. Endocrinol., April 1, 2007; 21(4): 817 - 828. [Abstract] [Full Text] [PDF]

				P. Carlsson, K. F. Koehler, and L. Nilsson Glucocorticoid Receptor Point Mutation V571M Facilitates Coactivator and Ligand Binding by Structural Rearrangement and Stabilization Mol. Endocrinol., August 1, 2005; 19(8): 1960 - 1977. [Abstract] [Full Text] [PDF]

				J. Zhang, J. Simisky, F. T. F. Tsai, and D. S. Geller A critical role of helix 3-helix 5 interaction in steroid hormone receptor function PNAS, February 22, 2005; 102(8): 2707 - 2712. [Abstract] [Full Text] [PDF]

				B. Kauppi, C. Jakob, M. Farnegardh, J. Yang, H. Ahola, M. Alarcon, K. Calles, O. Engstrom, J. Harlan, S. Muchmore, et al. The Three-dimensional Structures of Antagonistic and Agonistic Forms of the Glucocorticoid Receptor Ligand-binding Domain: RU-486 INDUCES A TRANSCONFORMATION THAT LEADS TO ACTIVE ANTAGONISM J. Biol. Chem., June 13, 2003; 278(25): 22748 - 22754. [Abstract] [Full Text] [PDF]

				R. Dey, P. Roychowdhury, and C. Mukherjee Homology modelling of the ligand-binding domain of glucocorticoid receptor: binding site interactions with cortisol and corticosterone Protein Eng. Des. Sel., August 1, 2001; 14(8): 565 - 571. [Abstract] [Full Text] [PDF]

				S. Arico, A. Petiot, C. Bauvy, P. F. Dubbelhuis, A. J. Meijer, P. Codogno, and E. Ogier-Denis The Tumor Suppressor PTEN Positively Regulates Macroautophagy by Inhibiting the Phosphatidylinositol 3-Kinase/Protein Kinase B Pathway J. Biol. Chem., September 14, 2001; 276(38): 35243 - 35246. [Abstract] [Full Text] [PDF]