Huntingtin's spherical solenoid structure enables polyglutamine tract-dependent modulation of its structure and function

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The polyglutamine expansion in huntingtin protein causes Huntington's disease. Here, we investigated structural and biochemical properties of huntingtin and the effect of the polyglutamine expansion using various biophysical experiments including circular dichroism, single particle electron microscopy and cross-linking mass spectrometry. Huntingtin is likely composed of five distinct domains and adopts a spherical alpha-helical solenoid where the amino-terminal and carboxyl-terminal regions fold to contain a circumscribed central cavity. Interestingly, we showed that the polyglutamine expansion increases alpha-helical properties of huntingtin and affects the intramolecular interactions among the domains. Our work delineates the structural characteristics of full-length huntingtin, which are affected by the polyglutamine expansion, and provides an elegant solution to the apparent conundrum of how the extreme amino-terminal polyglutamine tract confers a novel property on huntingtin, causing the disease
Publisher
ELIFE SCIENCES PUBLICATIONS LTD
Issue Date
2016-03
Language
English
Article Type
Article
Keywords

DISEASE GENE ALLELES; MASS-SPECTROMETRY; CAG REPEAT; IN-VIVO; TOXICITY; PROTEIN; PHOSPHORYLATION; EXPRESSION; COMPLEX; DOMAIN

Citation

ELIFE, v.5

ISSN
2050-084X
DOI
10.7554/eLife.11184
URI
http://hdl.handle.net/10203/208773
Appears in Collection
BS-Journal Papers(저널논문)
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