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

Albert Escobedo, Busra Topal, Micha B. A. Kunze, Juan Aranda, Giulio Chiesa, Daniele Mungianu, Ganeko Bernardo-Seisdedos, Bahareh Eftekharzadeh, Margarida Gairí, Roberta Pierattelli, Isabella C. Felli, Tammo Diercks, Oscar Millet, Jesús García, Modesto Orozco, Ramon Crehuet (), Kresten Lindorff-Larsen () and Xavier Salvatella ()
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Albert Escobedo: The Barcelona Institute of Science and Technology
Busra Topal: The Barcelona Institute of Science and Technology
Micha B. A. Kunze: University of Copenhagen
Juan Aranda: The Barcelona Institute of Science and Technology
Giulio Chiesa: The Barcelona Institute of Science and Technology
Daniele Mungianu: The Barcelona Institute of Science and Technology
Ganeko Bernardo-Seisdedos: CIC bioGUNE
Bahareh Eftekharzadeh: The Barcelona Institute of Science and Technology
Margarida Gairí: Scientific and Technological Centers University of Barcelona (CCiTUB)
Roberta Pierattelli: University of Florence
Isabella C. Felli: University of Florence
Tammo Diercks: CIC bioGUNE
Oscar Millet: CIC bioGUNE
Jesús García: The Barcelona Institute of Science and Technology
Modesto Orozco: The Barcelona Institute of Science and Technology
Ramon Crehuet: Institute for Advanced Chemistry of Catalonia (IQAC-CSIC)
Kresten Lindorff-Larsen: University of Copenhagen
Xavier Salvatella: The Barcelona Institute of Science and Technology

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09923-2

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