Mutant Exon1 Huntingtin Aggregation is Regulated by T3 Phosphorylation-Induced Structural Changes and Crosstalk between T3 Phosphorylation and Acetylation at K6.
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.
Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Institute of Physics of Biological Systems, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-, 1015, Lausanne, Switzerland.
Anass
A
Chiki
Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Institute of Physics of Biological Systems, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-, 1015, Lausanne, Switzerland.
Sean M
SM
DeGuire
The Laboratory of the Physics of Living Matter, Institute of Physics of Biological Systems, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-, 1015, Lausanne, Switzerland.|Current address: University of Cambridge, Department of Chemistry, Lensfield Road, Cambridge, CB2 1EW, UK.
Francesco S
FS
Ruggeri
MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW71AA, UK.
Domenico
D
Sanfelice
Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Institute of Physics of Biological Systems, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-, 1015, Lausanne, Switzerland.
Annalisa
A
Ansaloni
Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Institute of Physics of Biological Systems, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-, 1015, Lausanne, Switzerland.
Zhe-Ming
ZM
Wang
The Laboratory of the Physics of Living Matter, Institute of Physics of Biological Systems, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-, 1015, Lausanne, Switzerland.
Urszula
U
Cendrowska
Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Institute of Physics of Biological Systems, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-, 1015, Lausanne, Switzerland.
Ritwik
R
Burai
Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Institute of Physics of Biological Systems, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-, 1015, Lausanne, Switzerland.
Sophie
S
Vieweg
MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW71AA, UK.
Annalisa
A
Pastore
The Laboratory of the Physics of Living Matter, Institute of Physics of Biological Systems, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-, 1015, Lausanne, Switzerland.
Giovanni
G
Dietler
Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Institute of Physics of Biological Systems, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-, 1015, Lausanne, Switzerland.
Hilal A
HA
Lashuel
D000107:Acetylation; D005091:Exons / Q000235:genetics; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D066329:Protein Aggregates; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational
C086055:HTT protein, human; D000071058:Huntingtin Protein; D066329:Protein Aggregates
Huntington's disease; acetylation; fibrils; phosphorylation; semisynthesis