Polyglutamine expansion induced dynamic misfolding of Androgen Receptor

Heling, L. W. H. J.; Sheikhhassani, V.; Ng, J.; van Vliet, M.; Jimenez, A.; Alegre-Marti, A.; Woodard, J.; van Roon-Mom, W.; McEwan, I. J.; Estebanez-Perpina, E.; Mashaghi, A.

doi:10.1101/2024.12.19.629423

bioRxiv · 10.1101/2024.12.19.629423

Polyglutamine expansion induced dynamic misfolding of Androgen Receptor

Heling, L. W. H. J.·Sheikhhassani, V.·Ng, J.·van Vliet, M.·Jimenez, A.·Alegre-Marti, A.·Woodard, J.·van Roon-Mom, W.·McEwan, I. J.·Estebanez-Perpina, E.·Mashaghi, A.

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Abstract

Spinal bulbar muscular atrophy (SBMA) is caused by a polyglutamine expansion (pQe) in the N-terminal transactivation domain of 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 modelling, 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 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.

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Heling, L. W. H. J., Sheikhhassani, V., Ng, J., van Vliet, M., Jimenez, A., Alegre-Marti, A., Woodard, J., van Roon-Mom, W., McEwan, I. J., Estebanez-Perpina, E., Mashaghi, A.. 2024-12-22. Polyglutamine expansion induced dynamic misfolding of Androgen Receptor. https://doi.org/10.1101/2024.12.19.629423

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