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

Davies, P.; Watt, Kate; Kelly, Sharon M.; Clark, Caroline; Price, Nicholas C.; McEwan, Iain J.

doi:10.1677/jme-08-0042

Cited by 64 publications

(78 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, one common feature of these activator-binding domains, as well as those found in the Swi/Snf subunits Swi1 and Snf5 (51), is that they are located in close proximity to nearby polyglutamine or polyglutamine/ asparagine repeats. Since these glutamine-rich repeats are expected to be flexible (1,14,15), they may function to enhance accessibility or exposure of the activator-binding domains in the context of large coactivator complexes.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Mediator Recruitment by Tandem Gcn4 Activation Domains and Three Gal11 Activator-Binding Domains

Herbig

Warfield

Fish

et al. 2010

Molecular and Cellular Biology

133

View full text Add to dashboard Cite

Targets of the tandem Gcn4 acidic activation domains in transcription preinitiation complexes were identified by site-specific cross-linking. The individual Gcn4 activation domains cross-link to three common targets, Gal11/Med15, Taf12, and Tra1, which are subunits of four conserved coactivator complexes, Mediator, SAGA, TFIID, and NuA4. The Gcn4 N-terminal activation domain also cross-links to the Mediator subunit Sin4/Med16. The contribution of the two Gcn4 activation domains to transcription was gene specific and varied from synergistic to less than additive. Gcn4-dependent genes had a requirement for Gal11 ranging from 10-fold dependence to complete Gal11 independence, while the Gcn4-Taf12 interaction did not significantly contribute to the expression of any gene studied. Complementary methods identified three conserved Gal11 activatorbinding domains that bind each Gcn4 activation domain with micromolar affinity. These Gal11 activatorbinding domains contribute additively to transcription activation and Mediator recruitment at Gcn4-and Gal11-dependent genes. Although we found that the conserved Gal11 KIX domain contributes to Gal11 function, we found no evidence of specific Gcn4-KIX interaction and conclude that the Gal11 KIX domain does not function by specific interaction with Gcn4. Our combined results show gene-specific coactivator requirements, a surprising redundancy in activator-target interactions, and an activator-coactivator interaction mediated by multiple low-affinity protein-protein interactions.Activation of transcription, a key regulatory step in gene control, is the endpoint of many signal transduction pathways controlling cell growth, development, and the response to stress. Sequence-specific binding of transcription activators to gene regulatory regions initiates a cascade of events ultimately leading to the assembly of a functional transcription preinitiation complex (PIC) (52). This recruitment pathway involves the cooperative action of coactivator complexes and the transcription machinery (3,37,42,43,53). A subset of these coactivators (e.g., ATP-dependent remodelers and histone acetyltransferases) act to modify and remodel chromatin, allowing access of additional gene-specific factors and the transcription machinery to promoters, while other coactivators (e.g., SAGA, Mediator, and TFIID) directly interact with PolII and the general transcription factors to promote PIC assembly.Most of the activator-target interactions characterized to date involve activator-coactivator interactions rather than direct interactions with the general transcription factors (16,23,41,51,59,60,64,66), and individual activators are generally found to interact with multiple factors. However, for many of these activator-target contacts, it is not clear if the activatortarget contacts are promoter specific and why the requirement for specific coactivators varies at different promoters (12,43).The acidic transcription activators are an important and universal class of transcription factors that activate transcriptio...

show abstract

Section: Discussionmentioning

confidence: 99%

Mechanism of Mediator Recruitment by Tandem Gcn4 Activation Domains and Three Gal11 Activator-Binding Domains

Herbig

Warfield

Fish

et al. 2010

Molecular and Cellular Biology

133

View full text Add to dashboard Cite

show abstract

“…It may be that the amino-terminal region of the AR contains structural motifs that may contribute to its role in disease. The amino terminus of the AR, which includes the polyglutamine tract, has been shown to contain significant regions of intrinsically disordered structure (48), and polyglutamine expansion increases the ␣-helical content of the region (21). The FXXLF motif itself has been shown to form an amphipathic ␣-helix that binds to the AF-2 domain via a primary charge clamp (19).…”

Section: Discussionmentioning

confidence: 99%

“…Polyglutamine length has been shown to determine the rate of inclusion formation (20) and, in the case of AR, modulates the folding and structure of the amino-terminal domain (21). Generally, there appears to be a pathological threshold of 36 -40 glutamines that favors a conformational change from a random coil to a ␤-structure (22).…”

Section: Spinal and Bulbar Muscular Atrophy (Sbma)mentioning

confidence: 99%

An Interdomain Interaction of the Androgen Receptor Is Required for Its Aggregation and Toxicity in Spinal and Bulbar Muscular Atrophy

Orr

Montie

Liu

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

Polyglutamine expansion within the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA) and is associated with misfolded and aggregated species of the mutant AR. We showed previously that nuclear localization of the mutant AR was necessary but not sufficient for SBMA. Here we show that an interdomain interaction of the AR that is central to its function within the nucleus is required for AR aggregation and toxicity. Ligands that prevent the interaction between the amino-terminal FXXLF motif and carboxyl-terminal AF-2 domain (N/C interaction) prevented toxicity and AR aggregation in an SBMA cell model and rescued primary SBMA motor neurons from 5␣-dihydrotestosterone-induced toxicity. Moreover, genetic mutation of the FXXLF motif prevented AR aggregation and 5␣-dihydrotestosterone toxicity. Finally, selective androgen receptor modulators, which prevent the N/C interaction, ameliorated AR aggregation and toxicity while maintaining AR function, highlighting a novel therapeutic strategy to prevent the SBMA phenotype while retaining AR transcriptional function.Spinal and bulbar muscular atrophy (SBMA) 2 is an X-linked, slowly progressive, adult onset, neurodegenerative disease that primarily affects males. Symptoms include proximal limb weakness and muscle atrophy, fasciculations, tremor, dysphagia, and dysarthria (1). SBMA results from expansion of a polymorphic trinucleotide (CAG) repeat that encodes a polyglutamine (polyQ) tract near the amino terminus of the androgen receptor (AR) (2). Although many patients exhibit signs of androgen insensitivity, including gynecomastia, testicular atrophy, and infertility, loss of AR function is not the primary mechanistic basis for disease in SBMA (3). Rather, the presence of an expanded polyglutamine tract within the AR leads to its misfolding, aberrant cleavage, and accumulation (4, 5), although how these phenomena lead to neuronal dysfunction and death is unclear.SBMA is a member of a family of nine neurodegenerative diseases caused by an expanded polyglutamine tract; these include spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17, dentatorubral pallidoluysian atrophy, and Huntington disease (reviewed in Ref. 6). In addition to neuronal loss, a common pathogenic feature of this family of neurodegenerative diseases is the accumulation of misfolded and aggregated mutant protein in the affected neuronal populations. SBMA is characterized by the specific loss of lower motor neurons from the brainstem and anterior horn of the spinal cord (7). This neuronal loss, the formation of nuclear inclusions, and the subsequent symptoms of the disease depend on the binding of the polyglutamine-expanded AR to its ligands testosterone or 5␣-dihydrotestosterone (DHT) (8 -11).The AR is a transcription factor and a member of the nuclear receptor superfamily that is regulated by hormone binding. Unliganded AR is found in the cytoplasm in an aporeceptor complex that contains heat shock proteins (Hsc70, Hsp40, and Hsp90), p23, and immunophilins (12). Androgens such as testost...

show abstract

“…Since the protection provided by an osmolyte does not depend on specific chemical interactions with the macromolecules, in principle, any of the osmolytes should be capable of replacing each other, depending upon either endogenous or exogenous availability of particular osmolyte(s) [94]. Since the role of protein backbone is critical in determining thermodynamic stability and folding of proteins in osmolyte solutions [95][96][97][98][99], designing these small molecules (osmolytes) appears to be an excellent strategy and could be a critical step in preventing various critical proteins from misfolding or aggregating [6]. This may have far reaching consequences in understanding and preventing several deleterious diseases that are caused by protein misfolding/aggregation [100,101].…”

Section: Preventing Aggregation and Oligmoerization Of Amyloid-β Withmentioning

confidence: 99%

Protective Role of Methylene Blue in Alzheimer's Disease via Mitochondria and Cytochrome c Oxidase

Atamna

Kumar

2010

JAD

120

100

View full text Add to dashboard Cite

Abstract. The key cytopathologies in the brains of Alzheimer's disease (AD) patients include mitochondrial dysfunction and energy hypometabolism, which are likely caused by the accumulation of toxic species of amyloid-β (Aβ) peptides. This review discusses two potential approaches to delay the onset of AD. The first approach is use of diaminophenothiazines (e.g., methylene blue; MB) to prevent mitochondrial dysfunction and to attenuate energy hypometabolism. We have shown that MB increases heme synthesis, cytochrome c oxidase (complex IV), and mitochondrial respiration, which are impaired in AD brains. Consistently, MB is one of the most effective agents to delay senescence in normal human cells. A key action of MB appears to be enhancing mitochondrial function, which is achieved at nM concentrations. We propose that the cycling of MB between the reduced leucomethylene blue (MBH2) and the oxidized (MB) forms may explain, in part, the mitochondria-protecting activities of MB. The second approach is use of naturally occurring osmolytes to prevent the formation of toxic forms of Aβ. Osmolytes (e.g., taurine, carnosine) are brain metabolites typically accumulated in tissues at relatively high concentrations following stress conditions. Osmolytes enhance thermodynamic stability of proteins by stabilizing natively-folded protein conformation, thus preventing aggregation, without perturbing other cellular processes. Experimental evidence suggests that the level of carnosine is significantly lower in AD patients. Osmolytes may inhibit the formation of Aβ species in vivo, thus preventing the formation of soluble oligomers. Osmolytes are efficient antioxidants that may also increase neural resistance to Aβ. The potential significance of combining MB and osmolytes to treat AD are discussed.

show abstract

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

Cited by 64 publications

References 78 publications

Mechanism of Mediator Recruitment by Tandem Gcn4 Activation Domains and Three Gal11 Activator-Binding Domains

Mechanism of Mediator Recruitment by Tandem Gcn4 Activation Domains and Three Gal11 Activator-Binding Domains

An Interdomain Interaction of the Androgen Receptor Is Required for Its Aggregation and Toxicity in Spinal and Bulbar Muscular Atrophy

Protective Role of Methylene Blue in Alzheimer's Disease via Mitochondria and Cytochrome c Oxidase

Contact Info

Product

Resources

About