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Investigating crosstalk among PTMs provides novel insight into the structural basis underlying the differential effects of Nt17 PTMs on mutant Httex1 aggregation

Anass Chiki, Zhidian Zhang, Kolla Rajasekhar, Luciano A. Abriata, Iman Rostami, Lucien Krapp, Driss Boudeffa, View ORCID ProfileMatteo Dal Peraro, View ORCID ProfileHilal A. Lashuel
doi: https://doi.org/10.1101/2021.02.21.432155
Anass Chiki
aLaboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
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Zhidian Zhang
aLaboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
bLaboratory for Biomolecular Modeling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
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Kolla Rajasekhar
aLaboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
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Luciano A. Abriata
bLaboratory for Biomolecular Modeling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
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Iman Rostami
aLaboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
cLaboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institute, Villigen PSI CH-5232, Switzerland
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Lucien Krapp
bLaboratory for Biomolecular Modeling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
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Driss Boudeffa
aLaboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
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Matteo Dal Peraro
bLaboratory for Biomolecular Modeling, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
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  • ORCID record for Matteo Dal Peraro
  • For correspondence: hilal.lashuel@epfl.ch matteo.dalperaro@epfl.ch
Hilal A. Lashuel
aLaboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
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  • ORCID record for Hilal A. Lashuel
  • For correspondence: hilal.lashuel@epfl.ch matteo.dalperaro@epfl.ch
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Abstract

Post-translational modifications (PTMs) within the first 17 amino acids (Nt17) of the Huntingtin protein (Htt) have been shown to inhibit the aggregation and attenuate the toxicity of mutant Htt proteins in vitro and in various models of Huntington’s disease. Our group’s previous studies suggested that the Nt17 PTM code is a combinatorial code that involves a complex interplay between different PTMs. Here, we expand on these studies by investigating the effect of methionine 8 oxidation (oxM8) and crosstalk between this PTM and either lysine 6 acetylation (AcK6) or threonine 3 phosphorylation (pT3) on the aggregation of mutant Httex1. We show that M8 oxidation delays but does not inhibit the aggregation and has no effect on the final morphologies of mutant Httex1 aggregates. This delay in aggregation kinetics could be attributed to the transient accumulation of oligomeric aggregates, which disappear upon the formation of Httex1 oxM8 fibrils. Interestingly, the presence of both oxM8 and AcK6 resulted in dramatic inhibition of Httex1 fibrillization, whereas the presence of oxM8 did not influence the aggregation inhibitory effect of pT3. To gain insight into the structural basis underlying these proteins’ aggregation properties, we investigated the impact of each PTM and the combination of these PTMs on the conformational properties of the Nt17 peptide by circular dichroism spectroscopy and molecular dynamics simulation. These studies show that M8 oxidation decreases the helicity of the Nt17 in the presence or absence of PTMs and provides novel insight into the structural basis underlying the effects of different PTMs on mutant Httex1 aggregation. PTMs that lower the mutant Httex1 aggregation rate (oxM8, AcK6/oxM8, pT3, pT3/oxM8, and phosphorylation at Serine 13) result in stabilization and increased population of a short N-terminal helix (first eight residues) in Nt17 or decreased abundance of other helical forms, including long helix and short C-terminal helix. PTMs that did not alter the aggregation of mutant Httex1 exhibit a similar distribution of helical conformation as the unmodified peptides. These results show that the relative abundance of N- vs. C-terminal helical conformations and long helices, rather than the overall helicity of Nt17, better explains the effect of different Nt17 PTMs on mutant Httex1; thus, explaining the lack of correlation between the effect of PTMs on the overall helicity of Nt17 and mutant Httex1 aggregation in vitro. Taken together, our results provide novel structural insight into the differential effects of single PTMs and crosstalk between different PTMs in regulating mutant Httex1 aggregation.

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Competing Interest Statement

Dr. Hilal Lashuel is the Founder and CSO of ND BioSciences.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted February 21, 2021.
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Investigating crosstalk among PTMs provides novel insight into the structural basis underlying the differential effects of Nt17 PTMs on mutant Httex1 aggregation
Anass Chiki, Zhidian Zhang, Kolla Rajasekhar, Luciano A. Abriata, Iman Rostami, Lucien Krapp, Driss Boudeffa, Matteo Dal Peraro, Hilal A. Lashuel
bioRxiv 2021.02.21.432155; doi: https://doi.org/10.1101/2021.02.21.432155
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Investigating crosstalk among PTMs provides novel insight into the structural basis underlying the differential effects of Nt17 PTMs on mutant Httex1 aggregation
Anass Chiki, Zhidian Zhang, Kolla Rajasekhar, Luciano A. Abriata, Iman Rostami, Lucien Krapp, Driss Boudeffa, Matteo Dal Peraro, Hilal A. Lashuel
bioRxiv 2021.02.21.432155; doi: https://doi.org/10.1101/2021.02.21.432155

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