Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in a transcription factor
Polyglutamine peptides can form very stable helices stabilized by glutamine side chain to main chain hydrogen bonds, shown in purple, that are bifurcate with the conventional main chain to main chain hydrogen bonds stabilizing a-helices, shown in yellow.
Escobedo A, Topal B, Kunze MBA, Aranda J, Chiesa G, Mungianu D, Bernardo-Seisdedos G, Eftekharzadeh B, Gairi M, Pierattelli R, Felli IC, Diercks T, Millet O, Garcia J, Orozco M, Crehuet R, Lindorff-Larsen K, Salvatella X.
Nat Commun 2019 May; 10: 2034.
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 alpha-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.
PubMed: 31048691. Doi: 10.1038/s41467-019-09923-2. Free PMC article
