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Angew Chem Int Ed Engl. 2018 Mar 26;57(14):3598-3601. doi: 10.1002/anie.201711530. Epub 2018 Mar 7.

A General Strategy to Access Structural Information at Atomic Resolution in Polyglutamine Homorepeats.

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Centre de Biochimie Structurale (CBS), INSERM, CNRS, Université de Montpellier, 29 rue de Navacelles, 34090, Montpellier, France.
Laboratoire de Biologie Cellulaire et Moléculaire, (LBCM-EA4558 Vaccination Antiparasitaire), UFR Pharmacie, Université de Montpellier, Montpellier, France.


Homorepeat (HR) proteins are involved in key biological processes and multiple pathologies, however their high-resolution characterization has been impaired due to their homotypic nature. To overcome this problem, we have developed a strategy to isotopically label individual glutamines within HRs by combining nonsense suppression and cell-free expression. Our method has enabled the NMR investigation of huntingtin exon1 with a 16-residue polyglutamine (poly-Q) tract, and the results indicate the presence of an N-terminal α-helix at near neutral pH that vanishes towards the end of the HR. The generality of the strategy was demonstrated by introducing a labeled glutamine into a pathological version of huntingtin with 46 glutamines. This methodology paves the way to decipher the structural and dynamic perturbations induced by HR extensions in poly-Q-related diseases. Our approach can be extended to other amino acids to investigate biological processes involving proteins containing low-complexity regions (LCRs).


NMR spectroscopy; genetic code expansion; homorepeat proteins; huntingtin; protein structures

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