Evidence map›Paper›PMID 40371721›Full record

ArticleProtein science : a publication of the Protein Society2025

Polyglutamine expansion induced dynamic misfolding of androgen receptor.

Laurens W H J Heling, Vahid Sheikhhassani, Julian Ng, Morris van Vliet, Alba Jiménez-Panizo, Andrea Alegre-Martí, Jaie Woodard, Willeke van Roon-Mom, Iain J McEwan, Eva Estébanez-Perpiñá and 1 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Protein science : a publication of the Protein Society, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Polyglutamine expansion induced dynamic misfolding of androgen receptor.Protein science : a publication of the Protein Society · 2025
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors.

Laurens W H J HelingMedical Systems Biophysics and Bioengineering, Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.ORCID 0000-0001-7071-6352
Vahid SheikhhassaniMedical Systems Biophysics and Bioengineering, Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
Julian NgMedical Systems Biophysics and Bioengineering, Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
Morris van VlietMedical Systems Biophysics and Bioengineering, Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
Alba Jiménez-PanizoDepartment of Biochemistry and Molecular Biomedicine, Institute of Biomedicine (IBUB) of the University of Barcelona (UB), Barcelona, Spain.
Andrea Alegre-MartíDepartment of Biochemistry and Molecular Biomedicine, Institute of Biomedicine (IBUB) of the University of Barcelona (UB), Barcelona, Spain.
Jaie WoodardDepartment of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA.
Willeke van Roon-MomDepartment of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Iain J McEwanInstitute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, Scotland.
Eva Estébanez-PerpiñáDepartment of Biochemistry and Molecular Biomedicine, Institute of Biomedicine (IBUB) of the University of Barcelona (UB), Barcelona, Spain.ORCID 0000-0003-2687-5801
Alireza MashaghiMedical Systems Biophysics and Bioengineering, Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.ORCID 0000-0002-2157-1211

Funding

Muscular Dystrophy Association MDA62807Nederlandse Organisatie voor Wetenschappelijk Onderzoek OCENW.XS21.3.103
6 · The paper itself

Abstract

Spinal bulbar muscular atrophy (SBMA) is caused by a polyglutamine expansion (pQe) in the N-terminal transactivation domain of the human androgen receptor (AR-NTD), resulting in a combination of toxic gain- and loss-of-function mechanisms. The structural basis of these processes has not been resolved due to the disordered nature of the NTD, which hinders experimental analyses of its detailed conformations. Here, using extensive computational modeling, we show that AR-NTD forms dynamic compact regions, which upon pQe re-organize dynamically, mediated partly by direct pQ interaction with the Androgen N-Terminal Signature (ANTS) motif. The altered dynamics of the NTD result in a perturbation of interdomain interactions, with potential implications for the binding of the receptor protein to its response element. Oligomeric aggregation of the dynamic misfolded NTD exposes pQe, but blocks tau-5 and the FQNLF motif, which could lead to aberrant receptor transcriptional activity. These observations suggest a structural mechanism for AR dysfunction in SBMA.

Indexed as

PeptidesProtein FoldingReceptors, AndrogenBulbo-Spinal Atrophy, X-LinkedHumansModels, MolecularMolecular Dynamics SimulationAR protein, humanPeptidespolyglutamineReceptors, Androgenandrogen receptorintrinsically disordered proteinneuromuscular disorderpolyglutamine expansionspinal‐bulbar muscular atrophy

Identifiers

PMID40371721
PMCPMC12079482

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.