Flanking regions determine the structure of the poly-glutamine homo- repeat in huntingtin through mechanisms common among glutamine-rich human proteins - Archive ouverte HAL Access content directly
Journal Articles Structure Year : 2020

Flanking regions determine the structure of the poly-glutamine homo- repeat in huntingtin through mechanisms common among glutamine-rich human proteins

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Abstract

The causative agent of Huntington's disease, the poly-Q homo-repeat in the N-terminal region of huntingtin (httex1), is flanked by a 17-residue-long fragment (N17) and a proline-rich region (PRR), which promote and inhibit the aggregation propensity of the protein, respectively, by poorly understood mechanisms. Based on experimental data obtained from site-specifically labeled NMR samples, we derived an ensemble model of httex1 that identified both flanking regions as opposing poly-Q secondary structure promoters. While N17 triggers helicity through a promiscuous hydrogen bond network involving the side chains of the first glutamines in the poly-Q tract, the PRR promotes extended conformations in neighboring glutamines. Furthermore, a bioinformatics analysis of the human proteome showed that these structural traits are present in many human glutamine-rich proteins and that they are more prevalent in proteins with longer poly-Q tracts. Taken together, these observations provide the structural bases to understand previous biophysical and functional data on httex1.
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Dates and versions

hal-02893075 , version 1 (08-07-2020)

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Annika N Urbanek, Matija Popovic, Anna Morató, Alejandro N Estaña, Carlos A Elena-Real, et al.. Flanking regions determine the structure of the poly-glutamine homo- repeat in huntingtin through mechanisms common among glutamine-rich human proteins. Structure, 2020, 28 (7), pp.733-746.e5. ⟨10.1016/j.str.2020.04.008⟩. ⟨hal-02893075⟩
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