Probing the Huntingtin 1-17 membrane anchor on a phospholipid bilayer by using all-atom simulations

Biophysical Journal
Sébastien CôtéNormand Mousseau

Abstract

Mislocalization and aggregation of the huntingtin protein are related to Huntington's disease. Its first exon-more specifically the first 17 amino acids (Htt17)-is crucial for the physiological and pathological functions of huntingtin. It regulates huntingtin's activity through posttranslational modifications and serves as an anchor to membrane-containing organelles of the cell. Recently, structure and orientation of the Htt17 membrane anchor were determined using a combined solution and solid-state NMR approach. This prompted us to refine this model by investigating the dynamics and thermodynamics of this membrane anchor on a POPC bilayer using all-atom, explicit solvent molecular dynamics and Hamiltonian replica exchange. Our simulations are combined with various experimental measurements to generate a high-resolution atomistic model for the huntingtin Htt17 membrane anchor on a POPC bilayer. More precisely, we observe that the single α-helix structure is more stable in the phospholipid membrane than the NMR model obtained in the presence of dodecylphosphocholine detergent micelles. The resulting Htt17 monomer has its hydrophobic plane oriented parallel to the bilayer surface. Our results further unveil the key residues inter...Continue Reading

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Citations

Mar 10, 2016·Biophysical Journal·Vincent BinetteNormand Mousseau
Jul 28, 2016·Biophysical Journal·Maxmore ChaibvaJustin Legleiter
Nov 4, 2016·The Journal of Physical Chemistry. B·Jan DomańskiMark S P Sansom
Feb 9, 2017·Biochemistry·Adewale AdegbuyiroJustin Legleiter
Dec 20, 2014·Journal of Peptide Science : an Official Publication of the European Peptide Society·Burkhard Bechinger
Jul 3, 2021·International Journal of Molecular Sciences·Arnaud MarquetteBurkhard Bechinger
Apr 18, 2017·The Journal of Physical Chemistry. B·Leili ZhangRuhong Zhou
Dec 17, 2019·ACS Chemical Neuroscience·Sanda Nastasia Moldovean, Vasile Chiş

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