Allosteric interaction between the amino terminal domain and the ligand binding domain of NR2A

The androgen receptor interacts with the p160 coactivators via two surfaces, one in the ligand binding domain and one in the amino-terminal domain. The ligand binding domain interacts with the nuclear receptor signature motifs, whereas the amino-terminal domain has a high affinity for a specific glutamine-rich region in the p160s. We here describe the implication of two conserved motifs in the latter interaction. The amino-terminal domain of the androgen receptor is a very strong activation domain constituent of Tau5, which is mainly active in the absence of the ligand binding domain, and Tau1, which is only active in the presence of the ligand binding domain. Both domains are, however, implicated in the recruitment of the p160s. Mutation analysis of the p160s has shown that the relative contribution of the two recruitment mechanisms via the signature motifs or via the glutamine-rich region depend on the nature of the enhancers tested. We propose, therefore, that the androgen receptor-coactivator complex has several alternative conformations, depending partially on the context of the enhancer.

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Diverse roles of androgen receptor (AR) domains in AR-mediated signaling

Nuclear Receptor Signaling ◽

10.1621/nrs.06008 ◽

2008 ◽

Vol 6 (1) ◽

pp. nrs.06008 ◽

Cited By ~ 119

Author(s):

Frank Claessens ◽

Sarah Denayer ◽

Nora Van Tilborgh ◽

Stefanie Kerkhofs ◽

Christine Helsen ◽

...

Keyword(s):

Transcription Factor ◽

Androgen Receptor ◽

Ligand Binding ◽

Nuclear Receptors ◽

Steroid Receptors ◽

Binding Domain ◽

Hinge Region ◽

Amino Terminal ◽

Terminal Domain ◽

Amino Terminal Domain

Androgens control male sexual development and maintenance of the adult male phenotype. They have very divergent effects on their target organs like the reproductive organs, muscle, bone, brain and skin. This is explained in part by the fact that different cell types respond differently to androgen stimulus, even when all these responses are mediated by the same intracellular androgen receptor. To understand these tissue- and cell-specific readouts of androgens, we have to learn the many different steps in the transcription activation mechanisms of the androgen receptor (NR3C4). Like all nuclear receptors, the steroid receptors have a central DNA-binding domain connected to a ligand-binding domain by a hinge region. In addition, all steroid receptors have a relatively large amino-terminal domain. Despite the overall structural homology with other nuclear receptors, the androgen receptor has several specific characteristics which will be discussed here. This receptor can bind two types of androgen response elements (AREs): one type being similar to the classical GRE/PRE-type elements, the other type being the more divergent and more selective AREs. The hormone-binding domain has low intrinsic transactivation properties, a feature that correlates with the low affinity of this domain for the canonical LxxLL-bearing coactivators. For the androgen receptor, transcriptional activation involves the alternative recruitment of coactivators to different regions in the amino-terminal domain, as well as the hinge region. Finally, a very strong ligand-induced interaction between the amino-terminal domain and the ligand-binding domain of the androgen receptor seems to be involved in many aspects of its function as a transcription factor. This review describes the current knowledge on the structure-function relationships within the domains of the androgen receptor and tries to integrate the involvement of different domains, subdomains and motifs in the functioning of this receptor as a transcription factor with tissue- and cell-specific readouts.

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Interaction of the Androgen Receptor Ligand-Binding Domain with the N-Terminal Domain and with Coactivators

Androgen Action in Prostate Cancer ◽

10.1007/978-0-387-69179-4_16 ◽

2009 ◽

pp. 375-384 ◽

Cited By ~ 1

Author(s):

Jan Trapman

Keyword(s):

Androgen Receptor ◽

Ligand Binding ◽

Binding Domain ◽

Ligand Binding Domain ◽

Receptor Ligand ◽

Terminal Domain

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Evolution of human, chicken, alligator, frog and zebrafish mineralocorticoid receptors: Allosteric influence on steroid specificity

10.1101/151233 ◽

2017 ◽

Cited By ~ 2

Author(s):

Yoshinao Katsu ◽

Kaori Oka ◽

Michael E. Baker

Keyword(s):

Dna Binding ◽

Ligand Binding ◽

Binding Domain ◽

Ligand Binding Domain ◽

Full Length ◽

Dna Binding Domain ◽

Mineralocorticoid Receptors ◽

Terminal Domain ◽

Terrestrial Vertebrate ◽

Hinge Domain

AbstractWe studied the response to aldosterone, 11-deoxycorticosterone, 11-deoxycortisol, cortisol, corticosterone, progesterone, 19-norprogesterone and spironolactone of human, chicken, alligator, frog and zebrafish full-length mineralocorticoid receptors (MRs) and truncated MRs, lacking the N-terminal domain (NTD) and DNA-binding domain (DBD), in which the hinge domain and ligand binding domain (LBD) were fused to a GAL4-DBD. Compared to full-length MRs, some vertebrate MRs required higher steroid concentrations to activate GAL4-DBD-MR-hinge/LBD constructs. For example, 11-deoxycortisol activated all full-length vertebrate MRs, but did not activate truncated terrestrial vertebrate MRs and was an agonist for truncated zebrafish MR. Progesterone, 19-norProgesterone and spironolactone did not activate full-length and truncated human, alligator and frog MRs. However, at 10 nM, these steroids activated full-length chicken and zebrafish MRs; at 100 nM, these steroids had little activity for truncated chicken MRs, while retaining activity for truncated zebrafish MRs, evidence that regulation of progestin activation of chicken MR resides in NTD/DBD and of zebrafish MR in hinge-LBD. Zebrafish and chicken MRs contain a serine corresponding to Ser810 in human MR, required for its antagonism by progesterone, suggesting novel regulation of progestin activation of chicken and zebrafish MRs. Progesterone may be a physiological activator of chicken and zebrafish MRs.

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Activation Function 2 in the Human Androgen Receptor Ligand Binding Domain Mediates Interdomain Communication with the NH2-terminal Domain

Journal of Biological Chemistry ◽

10.1074/jbc.274.52.37219 ◽

1999 ◽

Vol 274 (52) ◽

pp. 37219-37225 ◽

Cited By ~ 246

Author(s):

Bin He ◽

Jon A. Kemppainen ◽

Johannes J. Voegel ◽

Hinrich Gronemeyer ◽

Elizabeth M. Wilson

Keyword(s):

Androgen Receptor ◽

Ligand Binding ◽

Activation Function ◽

Binding Domain ◽

Ligand Binding Domain ◽

Receptor Ligand ◽

Terminal Domain ◽

Human Androgen Receptor ◽

Interdomain Communication

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Structure/function analysis of the integrin beta 1 subunit by epitope mapping

The Journal of Cell Biology ◽

10.1083/jcb.122.6.1361 ◽

1993 ◽

Vol 122 (6) ◽

pp. 1361-1371 ◽

Cited By ~ 38

Author(s):

DT Shih ◽

JM Edelman ◽

AF Horwitz ◽

GB Grunwald ◽

CA Buck

Keyword(s):

Ligand Binding ◽

Epitope Mapping ◽

Transmembrane Domain ◽

Binding Domain ◽

Ligand Binding Domain ◽

Alpha Subunit ◽

Cell Surface Expression ◽

Regulatory Domain ◽

Ligand Specificity ◽

Amino Terminal

Monoclonal antibodies (mAbs) have been produced against the chicken beta 1 subunit that affect integrin functions, including ligand binding, alpha subunit association, and regulation of ligand specificity. Epitope mapping of these antibodies was used to identify regions of the subunit involved in these functions. To accomplish this, we produced mouse/chicken chimeric beta 1 subunits and expressed them in mouse 3T3 cells. These chimeric subunits were fully functional with respect to heterodimer formation, cell surface expression, and cell adhesion. They differed in their ability to react with a panel anti-chicken beta 1 mAbs. Epitopes were identified by a loss of antibody binding upon substitution of regions of the chicken beta 1 subunit by homologous regions of the mouse beta 1 subunit. The identification of the epitope was confirmed by a reciprocal exchange of chicken and mouse beta 1 domains that resulted in the gain of the ability of the mouse subunit to interact with a particular anti-chicken beta 1 mAb. Using this approach, we found that the epitopes for one set of antibodies that block ligand binding mapped toward the amino terminal region of the beta 1 subunit. This region is homologous to a portion of the ligand-binding domain of the beta 3 subunit. In addition, a second set of antibodies that either block ligand binding, alter ligand specificity, or induce alpha/beta subunit dissociation mapped to the cysteine rich repeats near the transmembrane domain of the molecule. These data are consistent with a model in which a portion of beta 1 ligand binding domain rests within the amino terminal 200 amino acids and a regulatory domain, that affects ligand binding through secondary changes in the structure of the molecule resides in a region of the subunit, possibly including the cysteine-rich repeats, nearer the transmembrane domain. The data also suggest the possibility that the alpha subunit may exert an influence on ligand specificity by interacting with this regulatory domain of the beta 1 subunit.

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The mGluR6 ligand-binding domain, but not the C-terminal domain, is required for synaptic localization in retinal ON-bipolar cells

Journal of Biological Chemistry ◽

10.1016/j.jbc.2021.101418 ◽

2021 ◽

pp. 101418

Author(s):

Melina A. Agosto ◽

Abiodun Adefola R. Adeosun ◽

Nitin Kumar ◽

Theodore G. Wensel

Keyword(s):

Ligand Binding ◽

Bipolar Cells ◽

Binding Domain ◽

Ligand Binding Domain ◽

Synaptic Localization ◽

Terminal Domain

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The Androgen Receptor Amino-Terminal Domain Plays a Key Role in p160 Coactivator-Stimulated Gene Transcription

Molecular and Cellular Biology ◽

10.1128/mcb.19.9.6085 ◽

1999 ◽

Vol 19 (9) ◽

pp. 6085-6097 ◽

Cited By ~ 190

Author(s):

Philippe Alen ◽

Frank Claessens ◽

Guido Verhoeven ◽

Wilfried Rombauts ◽

Ben Peeters

Keyword(s):

Androgen Receptor ◽

Mammalian Cells ◽

Transcriptional Activity ◽

Activation Function ◽

Binding Domain ◽

Functional Interaction ◽

Full Size ◽

Amino Terminal ◽

Terminal Domain ◽

Amino Terminal Domain

ABSTRACT Steroid receptors are conditional transcription factors that, upon binding to their response elements, regulate the expression of target genes via direct protein interactions with transcriptional coactivators. We have analyzed the functional interactions between the androgen receptor (AR) and 160-kDa nuclear receptor coactivators. Upon overexpression in mammalian cells, these coactivators enhance the transcriptional activity of both the amino-terminal domain (NTD) and the ligand-binding domain (LBD) of the AR. The coactivator activity for the LBD is strictly ligand-controlled and depends on the nature of the DNA-binding domain to which it is fused. We demonstrate that the NTD physically interacts with coactivators and with the LBD and that this interaction, like the functional interaction between the LBD and p160 coactivators, relies on the activation function 2 (AF2) core domain. The mutation of a highly conserved lysine residue in the predicted helix 3 of the LBD (K720A), however, blunts the functional interaction with coactivators but not with the NTD. Moreover, this mutation does not affect the transcriptional activity of the full-size AR. A mutation in the NTD of activation function AF1a (I182A/L183A), which dramatically impairs the activity of the AR, has no effect on the intrinsic transcriptional activity of the NTD but interferes with the cooperation between the NTD and the LBD. Finally, p160 proteins in which the three LXXLL motifs are mutated retain most of their coactivator activity for the full-size AR, although they are no longer functional for the isolated LBD. Together, these data suggest that in the native AR the efficient recruitment of coactivators requires a functional association of the NTD with the LBD and that the binding of coactivators occurs primarily through the NTD.

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