Induced α-Helix Structure in AF1 of the Androgen Receptor upon Binding Transcription Factor TFIIF

Kumar, Raj; Betney, Russell; Li, Jianquan; Thompson, E. Brad; McEwan, Iain J.

doi:10.1021/bi035934p

Cited by 103 publications

(97 citation statements)

References 40 publications

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“…An induced fit mechanism has been reported also for the activation domain of c-Myc specifically through interaction with TBP (21). Similar results have been reported for an interaction between a steroid receptor AF domain (AR AF1) and a coregulatory protein (27,44). Although limited, these data indicate that the activation domains of these transcription factors may be adopting a folded functional conformation under physiological conditions through interaction with coregulatory proteins of the transcriptional machinery complex.…”

Section: Discussionsupporting

confidence: 81%

TATA box binding protein induces structure in the recombinant glucocorticoid receptor AF1 domain

Kumar

Volk

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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A number of transcription factor proteins contain domains that are fully or partially unstructured. The means by which such proteins acquire naturally folded conformations are not well understood. When they encounter their proper binding partner(s), several of these proteins adopt a folded conformation through an induced-fit mechanism. The glucocorticoid receptor (GR) is a ligand-activated transcription factor. Expressed independently as a recombinant peptide, the N-terminal transactivation domain (AF1) of the GR shows little structure and appears to exist as a collection of random coil configurations. The GR AF1 is known to interact with other transcription factors, including a critical component of the general transcription machinery proteins, the TATA box binding protein (TBP). We tested whether this interaction can lead to acquisition of structure in the GR AF1. Our results show that recombinant GR AF1 acquires a significant amount of helical content when it interacts with TBP. These structural changes were monitored by Fourier transform infrared and NMR spectroscopies, and by proteolytic digestions. Our results support a model in which TBP binding interaction with the GR AF1 induces significantly greater helical structure in the AF1 domain. This increased helical content in the GR AF1 appears to come mostly at the expense of random coil conformation. These results are in accordance with the hypothesis that an induced-fit mechanism gives structure to the GR AF1 when it encounters TBP.glucocorticoid receptor ͉ N-terminal activation function ͉ coregulatory protein ͉ protein folding T he glucocorticoid receptor (GR) is a ligand-activated transcription factor with the domain structural arrangement typical of the nuclear hormone receptors superfamily (1-4). The GR regulates transcription of target genes by binding DNA at specific hormone response elements and͞or by interacting with other transcription factors (5-8). Although the structural organization of steroid receptors into N-terminal domain (NTD), DNA binding domain (DBD), and ligand binding domain is well characterized (9-14), precisely how transcription is regulated by them is largely unknown. For all steroid receptors, this is in part due to the lack of information about their transcription activating domain AF1, located in the NTD (9, 10). The GR AF1 sequence resembles those of acidic transactivation domains of several transcription factors (15, 16). When expressed independently, the GR AF1 shows little structure and seems to exist as an ensemble of largely unstructured conformers (17, 18). The GR AF1 is known to interact with other transcription factors, and conditional folding has been suggested to be the key for these interactions (19)(20)(21)(22).It has been reported that in the presence of trifluoroethanol, the ''core'' of AF1 (AF1 c , amino acids 187-242), located toward the C-terminal end of AF1, adopts three helical segments (17). Independent experiments have shown that substitution of the ␣-helixbreaking amino acid proline for natural residues a...

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Section: Discussionsupporting

confidence: 81%

TATA box binding protein induces structure in the recombinant glucocorticoid receptor AF1 domain

Kumar

Volk

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…We have recently reported on the induced folding of the AR-AF-1 transactivation domain in the presence of structure stabilising solutes and the binding partner TFIIF (Reid et al 2002, Kumar et al 2004. In the present study, we have extended these findings to include the entire AR-NTD and the influence of DNA binding on protein structure.…”

Section: Discussionmentioning

confidence: 67%

“…However, folding of this domain was observed in the presence of structure stabilising solutes and, crucially, upon binding the target protein TFIIF (Reid et al 2002, Kumar et al 2004. We were therefore interested to investigate the role of DNA binding on the folding of the AR-NTD and the influence of selective and non-selective DNA sequences.…”

Section: Ar-ntd Conformational Changes Upon Dna Bindingmentioning

confidence: 99%

Intra-domain communication between the N-terminal and DNA-binding domains of the androgen receptor: modulation of androgen response element DNA binding

Brodie¹,

McEwan

2005

Journal of Molecular Endocrinology

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The androgen receptor (AR) is a ligand-activated transcription factor that recognises and binds to specific DNA response elements upon activation by the steroids testosterone or dihydrotestosterone. In vitro, two types of response element have been characterised -non-selective elements that bind the androgen, glucocorticoid and progesterone receptors, and androgen receptor-selective sequences. In the present study, the allosteric effects of DNA binding on the receptor amino-terminal domain (NTD) were studied. Binding to both types of DNA response element resulted in changes in the intrinsic fluorescence emission spectrum for four tryptophan residues within the AR-NTD and resulted in a more protease-resistant conformation. In binding experiments, it was observed that the presence of the AR-NTD reduced the affinity of receptor polypeptides for binding to both selective and non-selective DNA elements derived from the probasin, PEM and prostatin C3 genes respectively, without significantly altering the protein-base pair contacts. Taken together, these results highlight the role of intra-domain communications between the AR-NTD and the DNA binding domain in receptor structure and function.

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“…These protein interactions were initially thought to be a mechanism for receptor contact with basal transcriptional machinery required for activation. However, a core C-terminal domain of human TBP consisting of aa 159 -339 (TBP C ) was reported to interact with the NTDs of several SRs and to promote a more compact tertiary structure with increased ␣-helical content (14,(33)(34)(35)(36). In the case of glucocorticoid (GR) and mineralocorticoid receptors (MR), TBP C binding was also observed to be associated with an enhancement of NTD-dependent transcriptional activity (30,31,33).…”

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confidence: 99%

Regulation of the Structurally Dynamic N-terminal Domain of Progesterone Receptor by Protein-induced Folding

Kumar

Moure²,

Khan

et al. 2013

Journal of Biological Chemistry

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Background:The mechanism of action of the N-terminal domain (NTD) of the progesterone receptor is not well understood. Results: We show the PR NTD adopts a functional folded conformation by undergoing disorder-order transition via binding to a target protein, TBP. Conclusion: This structural reorganization of the NTD facilitates binding of co-activators required for transcriptional activation. Significance: A novel mechanism of PR-dependent transcriptional activation is defined.

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Induced α-Helix Structure in AF1 of the Androgen Receptor upon Binding Transcription Factor TFIIF

Cited by 103 publications

References 40 publications

TATA box binding protein induces structure in the recombinant glucocorticoid receptor AF1 domain

TATA box binding protein induces structure in the recombinant glucocorticoid receptor AF1 domain

Intra-domain communication between the N-terminal and DNA-binding domains of the androgen receptor: modulation of androgen response element DNA binding

Regulation of the Structurally Dynamic N-terminal Domain of Progesterone Receptor by Protein-induced Folding

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