Computational Study of the Structure and Dynamics of Androgen Receptor Polyglutamine Tract
| Autor: | Topal, Busra |
|---|---|
| Přispěvatelé: | Salvatella i Giralt, Xavier, Universitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Hydrogen bonding
Glutamina Glutamine Malalties neurodegeneratives Dinámica molecular Enlaces de hidrógeno Neurodegenerative Diseases Molecular dynamics Ciències de la Salut Enfermedades neurodegenerativas Factores de transcripción Factors de transcripció Transcription factors Dinàmica molecular Enllaços d'hidrogen |
| Zdroj: | TDX (Tesis Doctorals en Xarxa) TDR. Tesis Doctorales en Red instname Dipòsit Digital de la UB Universidad de Barcelona |
| Popis: | [eng] Polyglutamine (polyQ) tracts are low sequence complexity regions frequently found in transcription factors. Abnormal expansions of polyQ tracts in nine different proteins cause a family of neurodegenerative disorders called polyQ diseases. Here we focus on the polyQ tract occurring in the intrinsically disordered N-terminal transactivation domain of the androgen receptor (AR). Expansion of this tract to the length of more than 37 residues causes neuromuscular disease spino bulbar muscular atrophy (SBMA), also known as Kennedy disease. Characterizing the conformational properties of polyQ tracts is crucial for understanding the molecular basis of polyQ diseases. 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 SBMA, depends on its length. Here we report that polyQ tract 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. |
| Databáze: | OpenAIRE |
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