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Efficient and Scalable Production of Full-length Human Huntingtin Variants in Mammalian Cells using a Transient Expression System
Published on: December 10, 2021
Polyglutamine expansion in huntingtin increases its insertion into lipid bilayers
Kimberly B Kegel1, Vitali Schewkunow, Ellen Sapp
1Department of Neurology, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA. kkegel@partners.org
Biochemical and Biophysical Research Communications
|July 18, 2009
Summary
Expanded polyglutamine (Q) tracts in huntingtin (htt) cause Huntington disease. Mutant htt with longer polyQ tracts inserts more into cell membranes, potentially disrupting their function.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Huntington disease is caused by expanded polyglutamine (Q) tracts in the huntingtin (htt) protein.
- Huntingtin protein associates with cell membranes, but the mechanism by which polyQ expansion affects membrane function in Huntington disease is unknown.
Purpose of the Study:
- To investigate the impact of polyQ expansion in huntingtin on its insertion into lipid bilayers.
- To elucidate the molecular mechanism by which mutant huntingtin may alter cellular membrane function.
Main Methods:
- Utilized differential scanning calorimetry to analyze the interaction of huntingtin protein fragments with synthetic lipid vesicles.
- Prepared vesicles composed of phosphatidylcholine and phosphatidylethanolamine.
- Tested interactions of htt amino acids 1-89 with varying polyQ lengths (20Q, 32Q, 53Q).
Main Results:
- GST-htt1-89 with a 53Q tract showed significantly greater insertion into synthetic lipid vesicles compared to constructs with 20Q or 32Q tracts.
- PolyQ expansion in huntingtin influences its membrane insertion properties.
Conclusions:
- Increased insertion of mutant huntingtin into cell membranes may lead to greater disorder within the lipid bilayer.
- This increased membrane disorder could be a key mechanism disturbing cellular membrane function in Huntington disease.
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