Structure of Membrane-Bound Huntingtin Exon 1 Reveals Membrane Interaction and Aggregation Mechanisms

Meixin Tao; Nitin K. Pandey; Ryan Barnes; Songi Han; Ralf Langen

doi:10.1016/j.str.2019.08.003

Structure of Membrane-Bound Huntingtin Exon 1 Reveals Membrane Interaction and Aggregation Mechanisms

Meixin Tao, Nitin K. Pandey, Ryan Barnes, Songi Han, Ralf Langen^*

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

31 Scopus citations

Abstract

Huntington's disease is caused by a polyQ expansion in the first exon of huntingtin (Httex1). Membrane interaction of huntingtin is of physiological and pathological relevance. Using electron paramagnetic resonance and Overhauser dynamic nuclear polarization, we find that the N-terminal residues 3–13 of wild-type Httex1(Q25) form a membrane-bound, amphipathic α helix. This helix is positioned in the interfacial region, where it is sensitive to membrane curvature and electrostatic interactions with head-group charges. Residues 14–22, which contain the first five residues of the polyQ region, are in a transition region that remains in the interfacial region without taking up a stable, α-helical structure. The remaining C-terminal portion is solvent exposed. The phosphomimetic S13D/S16D mutations, which are known to protect from toxicity, inhibit membrane binding and attenuate membrane-mediated aggregation of mutant Httex1(Q46) due to electrostatic repulsion. Targeting the N-terminal membrane anchor using post-translational modifications or specific binders could be a potential means to reduce aggregation and toxicity in vivo.

Original language	English (US)
Pages (from-to)	1570-1580.e4
Journal	Structure
Volume	27
Issue number	10
DOIs	https://doi.org/10.1016/j.str.2019.08.003
State	Published - Oct 1 2019

Funding

This study was supported by the National Institutes of Health ( R01NS084345 to R.L.) and ( R01GM116128 to S.H.). This work made use of shared facilities of the UCSB MRSEC ( NSF DMR 1720256 ), a member of the Materials Research Facilities Network ( www.mrfn.org ). Support for the ODNP studies was provided by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy – EXC-2033 – project number 390677874. This study was supported by the National Institutes of Health (R01NS084345 to R.L.) and (R01GM116128 to S.H.). This work made use of shared facilities of the UCSB MRSEC (NSF DMR 1720256), a member of the Materials Research Facilities Network (www.mrfn.org). Support for the ODNP studies was provided by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy ? EXC-2033 ? project number 390677874. R.L. and M.T. designed the experiments; M.T. N.K.P. and R.B. conducted the experiments; M.T. N.K.P. R.L. R.B. and S.H. performed data analyses; M.T. R.L. and S.H. wrote the manuscript with input from all authors. The authors declare no competing interests.

Keywords

EPR
Huntington's disease
ODNP
huntingtin exon 1
membrane-mediated aggregation
polyglutamine expansion
protein misfolding
protein-membrane interaction

ASJC Scopus subject areas

Structural Biology
Molecular Biology

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10.1016/j.str.2019.08.003

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title = "Structure of Membrane-Bound Huntingtin Exon 1 Reveals Membrane Interaction and Aggregation Mechanisms",

abstract = "Huntington's disease is caused by a polyQ expansion in the first exon of huntingtin (Httex1). Membrane interaction of huntingtin is of physiological and pathological relevance. Using electron paramagnetic resonance and Overhauser dynamic nuclear polarization, we find that the N-terminal residues 3–13 of wild-type Httex1(Q25) form a membrane-bound, amphipathic α helix. This helix is positioned in the interfacial region, where it is sensitive to membrane curvature and electrostatic interactions with head-group charges. Residues 14–22, which contain the first five residues of the polyQ region, are in a transition region that remains in the interfacial region without taking up a stable, α-helical structure. The remaining C-terminal portion is solvent exposed. The phosphomimetic S13D/S16D mutations, which are known to protect from toxicity, inhibit membrane binding and attenuate membrane-mediated aggregation of mutant Httex1(Q46) due to electrostatic repulsion. Targeting the N-terminal membrane anchor using post-translational modifications or specific binders could be a potential means to reduce aggregation and toxicity in vivo.",

keywords = "EPR, Huntington's disease, ODNP, huntingtin exon 1, membrane-mediated aggregation, polyglutamine expansion, protein misfolding, protein-membrane interaction",

author = "Meixin Tao and Pandey, \{Nitin K.\} and Ryan Barnes and Songi Han and Ralf Langen",

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",

year = "2019",

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doi = "10.1016/j.str.2019.08.003",

language = "English (US)",

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N2 - Huntington's disease is caused by a polyQ expansion in the first exon of huntingtin (Httex1). Membrane interaction of huntingtin is of physiological and pathological relevance. Using electron paramagnetic resonance and Overhauser dynamic nuclear polarization, we find that the N-terminal residues 3–13 of wild-type Httex1(Q25) form a membrane-bound, amphipathic α helix. This helix is positioned in the interfacial region, where it is sensitive to membrane curvature and electrostatic interactions with head-group charges. Residues 14–22, which contain the first five residues of the polyQ region, are in a transition region that remains in the interfacial region without taking up a stable, α-helical structure. The remaining C-terminal portion is solvent exposed. The phosphomimetic S13D/S16D mutations, which are known to protect from toxicity, inhibit membrane binding and attenuate membrane-mediated aggregation of mutant Httex1(Q46) due to electrostatic repulsion. Targeting the N-terminal membrane anchor using post-translational modifications or specific binders could be a potential means to reduce aggregation and toxicity in vivo.

AB - Huntington's disease is caused by a polyQ expansion in the first exon of huntingtin (Httex1). Membrane interaction of huntingtin is of physiological and pathological relevance. Using electron paramagnetic resonance and Overhauser dynamic nuclear polarization, we find that the N-terminal residues 3–13 of wild-type Httex1(Q25) form a membrane-bound, amphipathic α helix. This helix is positioned in the interfacial region, where it is sensitive to membrane curvature and electrostatic interactions with head-group charges. Residues 14–22, which contain the first five residues of the polyQ region, are in a transition region that remains in the interfacial region without taking up a stable, α-helical structure. The remaining C-terminal portion is solvent exposed. The phosphomimetic S13D/S16D mutations, which are known to protect from toxicity, inhibit membrane binding and attenuate membrane-mediated aggregation of mutant Httex1(Q46) due to electrostatic repulsion. Targeting the N-terminal membrane anchor using post-translational modifications or specific binders could be a potential means to reduce aggregation and toxicity in vivo.

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Structure of Membrane-Bound Huntingtin Exon 1 Reveals Membrane Interaction and Aggregation Mechanisms

Abstract

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Keywords

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