Reversible Amyloid Fiber Formation in the N Terminus of Androgen Receptor

Asencio-Hernández, Julia; Ruhlmann, Christine; McEwen, A.G.; Eberling, Pascal; Nominé, Yves; Céraline, Jocelyn; Starck, Jean-Philippe; Delsuc, Marc-André

doi:10.1002/cbic.201402420

Cited by 6 publications

(15 citation statements)

References 24 publications

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“…This was confirmed by transmission electron microscopy (TEM) analysis of the pelleted material in the NMR tube after the 24 h incubation. The resulting images displayed numerous fibrils with a large distribution of lengths but similar widths in agreement with our previous report [14]. …”

Section: Amyloidogenic Properties Of Kelckavsvsm Peptides Expressed Asupporting

confidence: 91%

“…We have previously shown that the KELCKAVSVSM forms fibrils under mild oxidation conditions [14]. We therefore determined whether the SUMO-KELCKAVSVSM fusion proteins (either in the monomer or dimer form) would form amyloid fibers but this failed after repeated attempts.…”

Section: Amyloidogenic Properties Of Kelckavsvsm Peptides Expressed Amentioning

confidence: 97%

“…We have previously reported amyloidogenic properties of a conserved sequence from the central region of AR-NTD [14]. These experiments, conducted with peptides of various lengths, identified the sequence KELCKAVSVSM as the minimal motif for the formation of amyloid fibers upon addition of 10% DMSO.…”

Section: Amyloidogenic Properties Of Kelckavsvsm Peptides Expressed Amentioning

confidence: 99%

“…We have recently shown that synthetic KELCKAVSVSM peptides derived from the AR NTD has an intrinsic property to form amyloid fibril under mild oxidative conditions [14]. It is therefore likely that this sequence would have an effect on aggregation of the polyQ track at the AR NTD.…”

Section: Introductionmentioning

confidence: 99%

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An Amyloidogenic Sequence at the N-Terminus of the Androgen Receptor Impacts Polyglutamine Aggregation

Oppong

Stier

Gaal

et al. 2017

Preprint

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Abstract:The human androgen receptor (AR) is a ligand inducible transcription factor harboring an amino terminal domain (AR-NTD) hosting the ligand independent activation function. AR-NTD is intrinsically disordered and display aggregation properties conferred by the presence of a poly-glutamine (polyQ) sequence of 22 residues. The length of the polyQ sequence, as well as the presence of adjacent sequence motifs modulate this aggregation property. AR-NTD contains also a conserved sequence motif KELCKAVSVSM that displays an intrinsic property to form amyloid fibrils under mild oxidative conditions of its conserved cysteine residue. As peptide sequences with intrinsic ability to oligomerize are reported to have an impact on the aggregation of polyQ tract, we determined the effect of the KELCKAVSVSM on the polyQ stretch in the context of the AR NTD, using Atomic Force Microscopy (AFM). Here, we present evidence for a crosstalk between the amyloidogenic properties of the KELCKAVSVSM motif and the polyQ stretch at the AR NTD.

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Section: Amyloidogenic Properties Of Kelckavsvsm Peptides Expressed Asupporting

confidence: 91%

Section: Amyloidogenic Properties Of Kelckavsvsm Peptides Expressed Amentioning

confidence: 97%

Section: Amyloidogenic Properties Of Kelckavsvsm Peptides Expressed Amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

An Amyloidogenic Sequence at the N-Terminus of the Androgen Receptor Impacts Polyglutamine Aggregation

Oppong

Stier

Gaal

et al. 2017

Preprint

Self Cite

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“…Hereafter, we refer to this 11 residue sequence as P11 . We have recently shown that the oxidation of Cys240 promoted the formation of peptide amyloid fibers, a process that can be reversed by the addition of a reducing agent such as tris(2-carboxyethyl)phosphine (TCEP) [13]. …”

Section: Introductionmentioning

confidence: 99%

NMR WaterLOGSY Reveals Weak Binding of Bisphenol A with Amyloid Fibers of a Conserved 11 Residue Peptide from Androgen Receptor

Asencio-Hernández¹,

Kieffer²,

Delsuc³

2016

PLoS ONE

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There is growing evidence that bisphenol A (BPA), a molecule largely released in the environment, has detrimental effects on ecosystems and on human health. It acts as an endocrine disruptor targeting steroid hormone receptors, such as the estrogen receptor (ER), estrogen-related receptor (ERR) and androgen receptor (AR). BPA-derived molecules have recently been shown to interact with the AR N-terminal domain (AR-NTD), which is known to be largely intrinsically disordered. This N-terminal domain contains an 11 residue conserved domain that forms amyloid fibers upon oxidative dimerisation through its strictly conserved Cys240 residue. We investigate here the interaction of BPA, and other potential endocrine disruptors, with AR-NTD amyloid fibers using the WaterLOGSY NMR experiment. We observed a selective binding of these compounds to the amyloid fibers formed by the AR-NTD conserved region and glutamine homopolymers. This observation suggests that the high potency of endocrine disruptors may result, in part, from their ability to bind amyloid forms of nuclear receptors in addition to their cognate binding sites. This property may be exploited to design future therapeutic strategies targeting AR related diseases such as the spinal bulbar muscular atrophy or prostate cancer. The ability of NMR WaterLOGSY experiments to detect weak interactions between small ligands and amyloid fibers may prove to be of particular interest for identifying promising hit molecules.

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Backbone 1H, 15N, 13C NMR assignment of the 518–627 fragment of the androgen receptor encompassing N-terminal and DNA binding domains

Meyer¹,

Wang²,

Pérez-Escrivà³

et al. 2016

Biomol NMR Assign

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Androgen receptor (AR) belongs to the nuclear receptor superfamily that are ligand dependent transcription factors. This protein binds to steroid hormones such as dihydrotestosterone, to specific DNA sequences as well as to a number of co-regulatory factors. A number of these interactions involve the N-terminal domain (NTD), that is predicted to be intrinsically disordered. In order to provide functional information about possible cross-talk mechanisms between the AR NTD and its DNA binding domain (DBD), we have undertaken the NMR study of a fragment of human AR encompassing the last 37 residues of the NTD and the DBD (NTD-DBD518-627). The backbone (1)H, (15)N, (13)C NMR resonance assignments of this fragment indicate the presence of residual helical secondary structure within the AR NTD.

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Reversible Amyloid Fiber Formation in the N Terminus of Androgen Receptor

Cited by 6 publications

References 24 publications

An Amyloidogenic Sequence at the N-Terminus of the Androgen Receptor Impacts Polyglutamine Aggregation

An Amyloidogenic Sequence at the N-Terminus of the Androgen Receptor Impacts Polyglutamine Aggregation

NMR WaterLOGSY Reveals Weak Binding of Bisphenol A with Amyloid Fibers of a Conserved 11 Residue Peptide from Androgen Receptor

Backbone 1H, 15N, 13C NMR assignment of the 518–627 fragment of the androgen receptor encompassing N-terminal and DNA binding domains

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