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

2008 ◽  
Vol 6 (1) ◽  
pp. nrs.06008 ◽  
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.

scholarly journals Characterization of the Two Coactivator-interacting Surfaces of the Androgen Receptor and Their Relative Role in Transcriptional Control*

2002 ◽  
Vol 277 (51) ◽  
pp. 49230-49237 ◽  
Author(s):  
Valerie Christiaens ◽  
Charlotte L. Bevan ◽  
Leen Callewaert ◽  
Anna Haelens ◽  
Guy Verrijdt ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Ligand Binding ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Relative Role ◽  
Rich Region ◽  
Amino Terminal ◽  
Terminal Domain ◽  
Amino Terminal Domain ◽  
Glutamine Rich Region

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.

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

2001 ◽  
Vol 4 (9) ◽  
pp. 894-901 ◽  
Author(s):  
F. Zheng ◽  
K. Erreger ◽  
C.-M. Low ◽  
T. Banke ◽  
C. J. Lee ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Binding Domain ◽  
Ligand Binding Domain ◽  
Amino Terminal ◽  
Allosteric Interaction ◽  
Terminal Domain ◽  
Amino Terminal Domain

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

1999 ◽  
Vol 19 (9) ◽  
pp. 6085-6097 ◽  
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.

scholarly journals SUN-LB138 Dynamic Structural Model of Testosterone Entry Into the Unliganded Androgen Receptor

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Irina Krylova ◽  
Fred J Schaufele ◽  
Christophe Guilbert
Keyword(s):  
Amino Acids ◽  
Androgen Receptor ◽  
Ligand Binding ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Binding Pocket ◽  
Binding Domain ◽  
Receptor Ligand ◽  
Ligand Binding Pocket ◽  
Crystallographic Structures

Abstract Background: Crystallographic structures of nuclear receptor ligand binding domains provide a static model of a receptor stably wrapped around an internalized ligand. Understanding the dynamics of a receptor at different stages of ligand binding has been hampered by the paucity of crystal structures for unliganded nuclear receptors. Molecular dynamic models have been constructed for some nuclear receptors to fill that void. Methods: The molecular simulation docking program MORDOR (MOlecular Recognition with a Driven dynamics OptimizeR)(1) was used to study the structural dynamics of the androgen receptor ligand binding domain (AR LBD) modeled from the static structure of the AR LBD bound to testosterone (T) (PDB ID: 2AM9). The goals of the study were to understand a) the dynamic interaction of the T in its binding pocket, b) AR LBD structural flexibilities that permit T entry/exit from the binding pocket and c) a model of the unliganded AR LBD. Results: Modeling AR LBD structure flexibility over time revealed possible alternative dynamic structures, including those without ligand, overlaid against the canonical nuclear receptor structure. The model dynamically tracks the structural changes as a ligand enters into the ligand binding domain and nestles into the ligand binding pocket. The model predicted the appearance of alpha helices within the AR LBD that transiently fold/unfold during the ligand entry phases. Once in the pocket, the ligand itself remains very dynamic in a still flexible pocket. The model predicted also AR LBD amino acids that sequentially interact with the ligand during its dynamic entry into the AR LBD. Intriguingly, those AR amino acids include those mutated in castration-resistant prostate tumors that continue to grow during androgen suppression therapy. Functional studies showed those mutant ARs had a primary consequence of enhancing response to lower level T, and other androgens, consistent with their role in creating a higher affinity AR that can scavenge low-level androgens in an androgen-suppressed patient. Conclusions: The molecular model of T binding to the AR LBD suggests a degree of structural dynamism not evident in the crystallographic structures commonly associated with nuclear receptors. Some AR mutations activating prostate tumor growth may do so by impacting androgen entry/exit, rather than by altering androgen fit into the ligand binding pocket. Reference: (1) Guilbert C, James TL (2008) J Chem Inf Model. 2008 48(6): 1257-1268. doi: 10.1021/ci8000327

scholarly journals Consequences of poly-glutamine repeat length for the conformation and folding of the androgen receptor amino-terminal domain

2008 ◽  
Vol 41 (5) ◽  
pp. 301-314 ◽  
Author(s):  
Philippa Davies ◽  
Kate Watt ◽  
Sharon M Kelly ◽  
Caroline Clark ◽  
Nicholas C Price ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Structural Changes ◽  
Muscular Atrophy ◽  
Cell Signalling ◽  
Limited Proteolysis ◽  
Amino Terminal ◽  
Terminal Domain ◽  
Helix Structure ◽  
Α Helix ◽  
Amino Terminal Domain

Poly-amino acid repeats, especially long stretches of glutamine (Q), are common features of transcription factors and cell-signalling proteins and are prone to expansion, resulting in neurodegenerative diseases. The amino-terminal domain of the androgen receptor (AR-NTD) has a poly-Q repeat between 9 and 36 residues, which when it expands above 40 residues results in spinal bulbar muscular atrophy. We have used spectroscopy and biochemical analysis to investigate the structural consequences of an expanded repeat (Q45) or removal of the repeat (ΔQ) on the folding of the AR-NTD. Circular dichroism spectroscopy revealed that in aqueous solution, the AR-NTD has a relatively limited amount of stable secondary structure. Expansion of the poly-Q repeat resulted in a modest increase in α-helix structure, while deletion of the repeat resulted in a small loss of α-helix structure. These effects were more pronounced in the presence of the structure-promoting solvent trifluoroethanol or the natural osmolyte trimethylamine N-oxide. Fluorescence spectroscopy showed that the microenvironments of four tryptophan residues were also altered after the deletion of the Q stretch. Other structural changes were observed for the AR-NTDQ45 polypeptide after limited proteolysis; in addition, this polypeptide not only showed enhanced binding of the hydrophobic probe 8-anilinonaphthalene-1-sulphonic acid but was more sensitive to urea-induced unfolding. Taken together, these findings support the view that the presence and length of the poly-Q repeat modulate the folding and structure of the AR-NTD.

scholarly journals Sintokamide A Is a Novel Antagonist of Androgen Receptor That Uniquely Binds Activation Function-1 in Its Amino-terminal Domain

2016 ◽  
Vol 291 (42) ◽  
pp. 22231-22243 ◽  
Author(s):  
Carmen A. Banuelos ◽  
Iran Tavakoli ◽  
Amy H. Tien ◽  
Daniel P. Caley ◽  
Nasrin R. Mawji ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Activation Function ◽  
Amino Terminal ◽  
Terminal Domain ◽  
Amino Terminal Domain

scholarly journals DNA recognition by the androgen receptor: evidence for an alternative DNA-dependent dimerization, and an active role of sequences flanking the response element on transactivation

2003 ◽  
Vol 369 (1) ◽  
pp. 141-151 ◽  
Author(s):  
Annemie HAELENS ◽  
Guy VERRIJDT ◽  
Leen CALLEWAERT ◽  
Valerie CHRISTIAENS ◽  
Kris SCHAUWAERS ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Dna Binding ◽  
Steroid Receptors ◽  
Binding Domain ◽  
Hinge Region ◽  
General Mechanism ◽  
Affinity Binding ◽  
Dna Binding Domain ◽  
Direct Repeats ◽  
Response Element

The androgen receptor has a subset of target DNA sequences, which are not recognized by any other steroid receptors. The androgen selectivity of these sequences was proposed to be the consequence of the ability of the androgen receptor to dimerize on direct repeats of 5′-TGTTCT-3′-like sequences. This is in contrast with the classical non-selective elements consisting of inverted repeats of the 5′-TGTTCT-3′ elements separated by three nucleotides and which are recognized by other steroid receptors in addition to the androgen receptor. We demonstrate that while the DNA-binding domain of the oestrogen receptor is unable to dimerize on direct repeats, dimeric binding can be rescued by replacing the second Zn finger and part of the hinge region by the corresponding fragment of the androgen receptor, but not the glucocorticoid receptor. In this study, we investigate the androgen receptor binding to all natural androgen-selective response elements described so far. We show that a 12-amino acid C-terminal extension of the DNA-binding domain is required for high-affinity binding of the androgen receptor to all these elements. For one androgen-specific low-affinity binding site, the flanking sequences do not contribute to the invitro affinity of the androgen receptor DNA-binding domain. Surprisingly, however, they control the transcriptional activity of the androgen receptor in transient transfection experiments. In conclusion, we give evidence that the alternative DNA-dependent dimerization of the androgen receptor on direct repeats is a general mechanism for androgen specificity in which the second Zn finger and hinge region are involved. In addition, the sequences flanking an androgen-response element can control the activity of the androgen receptor.

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