Yalinca, H;
Gehin, CJC;
Oleinikovas, V;
Lashuel, HA;
Gervasio, FL;
Pastore, A;
(2019)
The Role of Post-translational Modifications on the Energy Landscape of Huntingtin N-Terminus.
Frontiers in Molecular Biosciences
, 6
, Article 95. 10.3389/fmolb.2019.00095.
Preview |
Text
fmolb-06-00095.pdf - Published Version Download (1MB) | Preview |
Abstract
Huntington disease is a neurodegenerative disease characterized by a polymorphic tract of polyglutamine repeats in exon 1 of the huntingtin protein, which is thought to be responsible for protein aggregation and neuronal death. The polyglutamine tract is preceded by a 17-residue sequence that is intrinsically disordered. This region is subject to phosphorylation, acetylation and other post-translational modifications in vivo, which modulate its secondary structure, aggregation and, subcellular localization. We used Molecular Dynamics simulations with a novel Hamiltonian-replica-exchange-based enhanced sampling method, SWISH, and an optimal combination of water and protein force fields to study the effects of phosphorylation and acetylation as well as cross-talk between these modifications on the huntingtin N-terminus. The simulations, validated by circular dichroism, were used to formulate a mechanism by which the modifications influence helical conformations. Our findings have implications for understanding the structural basis underlying the effect of PTMs in the aggregation and cellular properties of huntingtin.
| Type: | Article |
|---|---|
| Title: | The Role of Post-translational Modifications on the Energy Landscape of Huntingtin N-Terminus |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3389/fmolb.2019.00095 |
| Publisher version: | https://doi.org/10.3389/fmolb.2019.00095 |
| Language: | English |
| Additional information: | This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| Keywords: | Huntington’s disease, misfolding disease, molecular dynamics, peptide folding, phosphorylation, post-translational modifications, enhanced sampling |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10083263 |
Archive Staff Only
 |
View Item |
