Huntingtin's spherical solenoid structure enables polyglutamine tract-dependent modulation of its structure and function
- The Maharaja Sayajirao University of Baroda, India
- McMaster University, Canada
- Eidgenössische Technische Hochschule Zürich, Switzerland
- Korea Advanced Institute of Science and Technology, Republic of Korea
- Massachusetts General Hospital, United States
- Universidad Autónoma de Querétaro, Mexico
- Karolinska Institute, Sweden
Abstract
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 α-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 α-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.
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Author details
Reviewing Editor
- Bart De Strooper, VIB Center for the Biology of Disease, KU Leuven, Belgium
Version history
- Received: August 29, 2015
- Accepted: March 13, 2016
- Accepted Manuscript published: March 22, 2016 (version 1)
- Version of Record published: April 5, 2016 (version 2)
Copyright
© 2016, Vijayvargia et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Huntingtin's spherical solenoid structure enables polyglutamine tract-dependent modulation of its structure and function
eLife 5:e11184.
https://doi.org/10.7554/eLife.11184
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