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

Anass Chiki, Sean M. Deguire, Francesco S. Ruggeri, Domenico Sanfelice, Annalisa Ansaloni, Zhe Ming Wang, Urszula Cendrowska, Ritwik Burai, Sophie Vieweg, Annalisa Pastore, Giovanni Dietler, Hilal A. Lashuel

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalAngewandte Chemie - International Edition
DOIs
Publication statusAccepted/In press - 2017

Fingerprint

Acetylation
Phosphorylation
Crosstalk
Agglomeration
Lysine
Post Translational Protein Processing
Pulse time modulation
Amino Acids
Conformations
Amino acids
Proteins

Keywords

  • Acetylation
  • Fibrils
  • Huntington's disease
  • Phosphorylation
  • Semisynthesis

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

Cite this

Mutant Exon1 Huntingtin Aggregation is Regulated by T3 Phosphorylation-Induced Structural Changes and Crosstalk between T3 Phosphorylation and Acetylation at K6. / Chiki, Anass; Deguire, Sean M.; Ruggeri, Francesco S.; Sanfelice, Domenico; Ansaloni, Annalisa; Wang, Zhe Ming; Cendrowska, Urszula; Burai, Ritwik; Vieweg, Sophie; Pastore, Annalisa; Dietler, Giovanni; Lashuel, Hilal A.

In: Angewandte Chemie - International Edition, 2017.

Research output: Contribution to journalArticle

Chiki, Anass ; Deguire, Sean M. ; Ruggeri, Francesco S. ; Sanfelice, Domenico ; Ansaloni, Annalisa ; Wang, Zhe Ming ; Cendrowska, Urszula ; Burai, Ritwik ; Vieweg, Sophie ; Pastore, Annalisa ; Dietler, Giovanni ; Lashuel, Hilal A. / Mutant Exon1 Huntingtin Aggregation is Regulated by T3 Phosphorylation-Induced Structural Changes and Crosstalk between T3 Phosphorylation and Acetylation at K6. In: Angewandte Chemie - International Edition. 2017.
@article{7f16e925d2ba41ea9caddeadd52a826c,
title = "Mutant Exon1 Huntingtin Aggregation is Regulated by T3 Phosphorylation-Induced Structural Changes and Crosstalk between T3 Phosphorylation and Acetylation at K6",
abstract = "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 = "Acetylation, Fibrils, Huntington's disease, Phosphorylation, Semisynthesis",
author = "Anass Chiki and Deguire, {Sean M.} and Ruggeri, {Francesco S.} and Domenico Sanfelice and Annalisa Ansaloni and Wang, {Zhe Ming} and Urszula Cendrowska and Ritwik Burai and Sophie Vieweg and Annalisa Pastore and Giovanni Dietler and Lashuel, {Hilal A.}",
year = "2017",
doi = "10.1002/anie.201611750",
language = "English",
journal = "Angewandte Chemie - International Edition",
issn = "1433-7851",
publisher = "John Wiley and Sons Ltd",

}

TY - JOUR

T1 - Mutant Exon1 Huntingtin Aggregation is Regulated by T3 Phosphorylation-Induced Structural Changes and Crosstalk between T3 Phosphorylation and Acetylation at K6

AU - Chiki, Anass

AU - Deguire, Sean M.

AU - Ruggeri, Francesco S.

AU - Sanfelice, Domenico

AU - Ansaloni, Annalisa

AU - Wang, Zhe Ming

AU - Cendrowska, Urszula

AU - Burai, Ritwik

AU - Vieweg, Sophie

AU - Pastore, Annalisa

AU - Dietler, Giovanni

AU - Lashuel, Hilal A.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Acetylation

KW - Fibrils

KW - Huntington's disease

KW - Phosphorylation

KW - Semisynthesis

UR - http://www.scopus.com/inward/record.url?scp=85016020931&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85016020931&partnerID=8YFLogxK

U2 - 10.1002/anie.201611750

DO - 10.1002/anie.201611750

M3 - Article

JO - Angewandte Chemie - International Edition

JF - Angewandte Chemie - International Edition

SN - 1433-7851

ER -