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Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in a transcription factor
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Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in a transcription factor
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Journal Article
Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in a transcription factor
2019
Overview
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.
Polyglutamine (polyQ) tracts are low-complexity regions and their expansion is linked to certain neurodegenerative diseases. Here the authors combine experimental and computational approaches to find that the length of the androgen receptor polyQ tract correlates with its helicity and show that the polyQ helical structure is stabilized by hydrogen bonds between the Gln side chains and main chain carbonyl groups.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 119/118
/ 82/80
/ 82/83
/ Atrophy
/ Bonding
/ Bulbo-Spinal Atrophy, X-Linked - genetics
/ Bulbo-Spinal Atrophy, X-Linked - pathology
/ Chains
/ Helices
/ Helicity
/ Humanities and Social Sciences
/ Humans
/ Hydrogen
/ Magnetic Resonance Spectroscopy
/ Molecular Dynamics Simulation
/ Mutation
/ Protein Aggregates - genetics
/ Protein Conformation, alpha-Helical - genetics
/ Receptors, Androgen - chemistry
/ Receptors, Androgen - genetics
/ Science
/ Spinal and bulbar muscular atrophy
/ Transcription Factors - chemistry
