AUTHOR=Yalinca Havva , Gehin Charlotte Julie Caroline , Oleinikovas Vladimiras , Lashuel Hilal A. , Gervasio Francesco Luigi , Pastore Annalisa TITLE=The Role of Post-translational Modifications on the Energy Landscape of Huntingtin N-Terminus JOURNAL=Frontiers in Molecular Biosciences VOLUME=6 YEAR=2019 URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2019.00095 DOI=10.3389/fmolb.2019.00095 ISSN=2296-889X 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.