Mutant Exon1 Huntingtin Aggregation is Regulated by T3 Phosphorylation-Induced Structural Changes and Crosstalk between T3 Phosphorylation and Acetylation at K6

Angew Chem Int Ed Engl. 2017 May 2;56(19):5202-5207. doi: 10.1002/anie.201611750. Epub 2017 Mar 23.


Herein, we used protein semisynthesis to investigate, for the first time, the effect of lysine acetylation and phosphorylation, as well as the crosstalk between these modifications on the structure and aggregation of mutant huntingtin exon1 (Httex1). Our results demonstrate that phosphorylation at T3 stabilizes the α-helical conformation of the N-terminal 17 amino acids (Nt17) and significantly inhibits the aggregation of mutant Httex1. Acetylation of single lysine residues, K6, K9 or K15, had no effect on Httex1 aggregation. Interestingly, acetylation at K6, but not at K9 or K15, reversed the inhibitory effect of T3 phosphorylation. Together, our results provide novel insight into the role of Nt17 post-translational modifications in regulating the structure and aggregation of Httex1 and suggest that its aggregation and possibly its function(s) are controlled by regulatory mechanisms involving crosstalk between different PTMs.

Keywords: Huntington's disease; acetylation; fibrils; phosphorylation; semisynthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Exons / genetics
  • Humans
  • Huntingtin Protein / genetics
  • Huntingtin Protein / metabolism*
  • Mutation
  • Phosphorylation
  • Protein Aggregates
  • Protein Conformation
  • Protein Processing, Post-Translational


  • HTT protein, human
  • Huntingtin Protein
  • Protein Aggregates