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 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 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.

scholarly journals Dual androgen receptor ( AR ) and STAT 3 inhibition by a compound targeting the AR amino‐terminal domain

2018 ◽  
Vol 6 (6) ◽  
pp. e00437 ◽  
Author(s):  
Yaping Hua ◽  
Waqas Azeem ◽  
Yunheng Shen ◽  
Shoude Zhang ◽  
Jan R. Olsen ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Amino Terminal ◽  
Terminal Domain ◽  
Amino Terminal Domain

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.

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