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Title: Secondary Structure of Huntingtin Amino-Terminal Region

Abstract

Huntington's disease is a genetic neurodegenerative disorder resulting from polyglutamine (polyQ) expansion (>36Q) within the first exon of Huntingtin (Htt) protein. We applied X-ray crystallography to determine the secondary structure of the first exon (EX1) of Htt17Q. The structure of Htt17Q-EX1 consists of an amino-terminal {alpha} helix, poly17Q region, and polyproline helix formed by the proline-rich region. The poly17Q region adopts multiple conformations in the structure, including {alpha} helix, random coil, and extended loop. The conformation of the poly17Q region is influenced by the conformation of neighboring protein regions, demonstrating the importance of the native protein context. We propose that the conformational flexibility of the polyQ region observed in our structure is a common characteristic of many amyloidogenic proteins. We further propose that the pathogenic polyQ expansion in the Htt protein increases the length of the random coil, which promotes aggregation and facilitates abnormal interactions with other proteins in cells.

Authors:
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Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1006178
Resource Type:
Journal Article
Journal Name:
Structure
Additional Journal Information:
Journal Volume: 17; Journal Issue: (9) ; 09, 2009
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; CRYSTALLOGRAPHY; DISEASES; EXONS; FLEXIBILITY; GENETICS; PROTEINS

Citation Formats

Kim, Mee Whi, Chelliah, Yogarany, Kim, Sang Woo, Otwinowski, Zbyszek, Bezprozvanny, Ilya, and UTSMC). Secondary Structure of Huntingtin Amino-Terminal Region. United States: N. p., 2010. Web. doi:10.1016/j.str.2009.08.002.
Kim, Mee Whi, Chelliah, Yogarany, Kim, Sang Woo, Otwinowski, Zbyszek, Bezprozvanny, Ilya, & UTSMC). Secondary Structure of Huntingtin Amino-Terminal Region. United States. doi:10.1016/j.str.2009.08.002.
Kim, Mee Whi, Chelliah, Yogarany, Kim, Sang Woo, Otwinowski, Zbyszek, Bezprozvanny, Ilya, and UTSMC). Tue . "Secondary Structure of Huntingtin Amino-Terminal Region". United States. doi:10.1016/j.str.2009.08.002.
@article{osti_1006178,
title = {Secondary Structure of Huntingtin Amino-Terminal Region},
author = {Kim, Mee Whi and Chelliah, Yogarany and Kim, Sang Woo and Otwinowski, Zbyszek and Bezprozvanny, Ilya and UTSMC)},
abstractNote = {Huntington's disease is a genetic neurodegenerative disorder resulting from polyglutamine (polyQ) expansion (>36Q) within the first exon of Huntingtin (Htt) protein. We applied X-ray crystallography to determine the secondary structure of the first exon (EX1) of Htt17Q. The structure of Htt17Q-EX1 consists of an amino-terminal {alpha} helix, poly17Q region, and polyproline helix formed by the proline-rich region. The poly17Q region adopts multiple conformations in the structure, including {alpha} helix, random coil, and extended loop. The conformation of the poly17Q region is influenced by the conformation of neighboring protein regions, demonstrating the importance of the native protein context. We propose that the conformational flexibility of the polyQ region observed in our structure is a common characteristic of many amyloidogenic proteins. We further propose that the pathogenic polyQ expansion in the Htt protein increases the length of the random coil, which promotes aggregation and facilitates abnormal interactions with other proteins in cells.},
doi = {10.1016/j.str.2009.08.002},
journal = {Structure},
number = (9) ; 09, 2009,
volume = 17,
place = {United States},
year = {2010},
month = {9}
}