Structural Model of the Proline-Rich Domain of Huntingtin Exon-1 Fibrils.

Abstract:

:Huntington's disease is a heritable neurodegenerative disease that is caused by a CAG expansion in the first exon of the huntingtin gene. This expansion results in an elongated polyglutamine domain that increases the propensity of huntingtin exon-1 to form cross-β fibrils. Although the polyglutamine domain is important for fibril formation, the dynamic, C-terminal proline-rich domain (PRD) of huntingtin exon-1 makes up a large fraction of the fibril surface. Because potential fibril toxicity has to be mediated by interactions of the fibril surface with its cellular environment, we wanted to model the conformational space adopted by the PRD. We ran 800-ns long molecular dynamics simulations of the PRD using an explicit water model optimized for intrinsically disordered proteins. These simulations accurately predicted our previous solid-state NMR data and newly acquired electron paramagnetic resonance double electron-electron resonance distances, lending confidence in their accuracy. The simulations show that the PRD generally forms an imperfect polyproline (polyP) II helical conformation. The two polyP regions within the PRD stay in a polyP II helix for most of the simulation, whereas occasional kinks in the proline-rich linker region cause an overall bend in the PRD structure. The dihedral angles of the glycine at the end of the second polyP region are very variable, effectively decoupling the highly dynamic 12 C-terminal residues from the rest of the PRD.

journal_name

Biophys J

journal_title

Biophysical journal

authors

Falk AS,Bravo-Arredondo JM,Varkey J,Pacheco S,Langen R,Siemer AB

doi

10.1016/j.bpj.2020.10.010

subject

Has Abstract

pub_date

2020-11-17 00:00:00

pages

2019-2028

issue

10

eissn

0006-3495

issn

1542-0086

pii

S0006-3495(20)30812-2

journal_volume

119

pub_type

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