Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in a transcription factor

Albert Escobedo,Daniele Mungianu,Bahareh Eftekharzadeh,Ramon Crehuet,Isabella C Felli,Kresten Lindorff-Larsen,Giulio Chiesa,Ganeko Bernardo-Seisdedos,Margarida Gairí,Xavier Salvatella,Jesús García,Oscar Millet,Busra Topal,Juan Aranda,Micha B A Kunze,Roberta Pierattelli,Modesto Orozco,Tammo Diercks

doi:10.1038/s41467-019-09923-2

Abstract

Polyglutamine (polyQ) tracts are regions of low sequence complexity frequently found in transcription factors. Tract length often correlates with transcriptional activity and expansion beyond specific thresholds in certain human proteins is the cause of polyQ disorders. 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 spinobulbar muscular atrophy (SBMA), depends on its length. Here we report that this sequence 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.

Highlights

Polyglutamine tracts are regions of low sequence complexity frequently found in transcription factors
The androgen receptor (AR, 919 residues) is the nuclear receptor that regulates the development of the male phenotype. It harbors a polyQ tract whose helical propensity—that we have recently revealed by nuclear magnetic resonance (NMR) and circular dichroism (CD)20—increases upon expansion[20,21]
Our results suggest explanations for how changes in polyQ tract length alter the transcriptional activity of AR and its propensity to aggregate in spinobulbar muscular atrophy (SBMA), providing plausible rationales for the range of tract lengths observed in men

Summary

Introduction

Polyglutamine (polyQ) tracts are regions of low sequence complexity frequently found in transcription factors. Tract length often correlates with transcriptional activity and expansion beyond specific thresholds in certain human proteins is the cause of polyQ disorders. Polyglutamine (polyQ) tracts are low-complexity regions that are composed almost exclusively of Gln residues They are frequent in the human proteome, in the intrinsically disordered domains of proteins involved in the regulation of transcription, such as the activation domains of transcription factors[1]. Most experimental studies carried out to date report that polyQ tracts are collapsed disordered coils that barely change conformation upon expansion[18]. These observations led to an alternative hypothesis that proposes that expansion leads to toxicity by increasing the affinity of polyQ tracts for their interactors, regardless of conformation[19]

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