Regulation of Androgen Receptor Activity by Transient Interactions of Its Transactivation Domain with General Transcription Regulators

Mol, Eva De; Szulc, Elzbieta; Sanza, Claudio Di; Martínez-Cristóbal, Paula; Bertoncini, Carlos W.; Fenwick, R. Bryn; Frigolé-Vivas, Marta; Masin, Marianela; Hunter, Irene; Buzón, Víctor; Brun-Heath, Isabelle; García, Jesús; Fabritiis, Gianni De; Estébanez‐Perpiñá, Eva; McEwan, Iain J.; Nebreda, Ángel R.; Salvatella, Xavier

doi:10.1016/j.str.2017.11.007

Cited by 45 publications

(28 citation statements)

References 48 publications

(71 reference statements)

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“…The structures of the DBD and LBD bound to their ligands have been characterized by X-ray crystallography 24–27 . The NTD is intrinsically disordered 28 , but solution nuclear magnetic resonance (NMR) spectroscopy has shown that it is rich in secondary structure, especially in regions key for transactivation 29,30 . The NTD of AR is one of the longest in the human SHR family and it includes the polyQ tract, starting at residue 58, which becomes expanded in SBMA 17 .…”

Section: Introductionmentioning

confidence: 99%

Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor

et al. 2019

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Molecular chaperones such as Hsp40 and Hsp70 hold the androgen receptor (AR) in an inactive conformation. They are released in the presence of androgens, enabling transactivation and causing the receptor to become aggregation-prone. Here we show that these molecular chaperones recognize a region of the AR N-terminal domain (NTD), including a FQNLF motif, that interacts with the AR ligand-binding domain (LBD) upon activation. This suggests that competition between molecular chaperones and the LBD for the FQNLF motif regulates AR activation. We also show that, while the free NTD oligomerizes, binding to Hsp70 increases its solubility. Stabilizing the NTD-Hsp70 interaction with small molecules reduces AR aggregation and promotes its degradation in cellular and mouse models of the neuromuscular disorder spinal bulbar muscular atrophy. These results help resolve the mechanisms by which molecular chaperones regulate the balance between AR aggregation, activation and quality control.

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Section: Introductionmentioning

confidence: 99%

Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor

et al. 2019

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“…Our results provide a plausible rationale as they suggest that variations in the length of polyQ tracts result in changes in the secondary structure of the transactivation domain of transcription factors. Indeed, such variations can affect the strength of the protein–protein interactions 52 , particularly of those regulating transcription 53 , which include interactions with transcriptional co-regulators and with general transcription factors. Whether a certain change in tract length causes a decrease or an increase in activity might depend on whether the polyQ tract and its flanking regions are involved in interactions with transcriptional co-activators or co-repressors and should therefore be context-dependent, as found experimentally 51,54 .…”

Section: Discussionmentioning

confidence: 99%

Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in a transcription factor

Escobedo¹,

Topal²,

Kunze³

et al. 2019

Nat Commun

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Polyglutamine (polyQ) tracts are regions of low sequence complexity frequently found in transcription factors. Tract length often correlates with transcriptional activity and expansion beyond specific thresholds in certain human proteins is the cause of polyQ disorders. To study the structural basis of the association between tract length, transcriptional activity and disease, we addressed how the conformation of the polyQ tract of the androgen receptor, associated with spinobulbar muscular atrophy (SBMA), depends on its length. Here we report that this sequence folds into a helical structure stabilized by unconventional hydrogen bonds between glutamine side chains and main chain carbonyl groups, and that its helicity directly correlates with tract length. These unusual hydrogen bonds are bifurcate with the conventional hydrogen bonds stabilizing α-helices. Our findings suggest a plausible rationale for the association between polyQ tract length and androgen receptor transcriptional activity and have implications for establishing the mechanistic basis of SBMA.

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“…Similarly, studies of translational isoforms with variable lengths of the GR-NTD have also found two coupled but thermodynamically distinct regions (Brinkmann et al 1989, Michigami et al 1999, Li et al 2012. At least in the case of these two oxosteroid receptors, the main determinants for transactivation map to their highly similar AF-1 sites (46% sequence identity; Kumar et al 2004, McEwan et al 2007, De Mol et al 2018.…”

Section: Figurementioning

confidence: 95%

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

Jiménez-Panizo

Pérez

Rojas

et al. 2019

Endocrine-Related Cancer

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Nuclear receptors are transcription factors that play critical roles in development, homeostasis and metabolism in all multicellular organisms. An important family of nuclear receptors comprises those members that respond to steroid hormones, and which is subdivided in turn into estrogen receptor (ER) isoforms α and β (NR3A1 and A2, respectively), and a second subfamily of so-called oxosteroid receptors. The latter includes the androgen receptor (AR/NR3C4), the glucocorticoid receptor (GR/NR3C1), the mineralocorticoid receptor (MR/NR3C2) and the progesterone receptor (PR/NR3C3). Here we review recent advances in our understanding of the structure-and-function relationship of steroid nuclear receptors and discuss their implications for the etiology of human diseases. We focus in particular on the role played by AR dysregulation in both prostate cancer (PCa) and androgen insensitivity syndromes (AIS), but also discuss conditions linked to mutations of the GR gene as well as those in a non-steroidal receptor, the thyroid hormone receptor (TR). Finally, we explore how these recent results might be exploited for the development of novel and selective therapeutic strategies.

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Regulation of Androgen Receptor Activity by Transient Interactions of Its Transactivation Domain with General Transcription Regulators

Cited by 45 publications

References 48 publications

Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor

Hsp70 and Hsp40 inhibit an inter-domain interaction necessary for transcriptional activity in the androgen receptor

Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in a transcription factor

Non-canonical dimerization of the androgen receptor and other nuclear receptors: implications for human disease

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