Secondary Structure of Huntingtin Amino-Terminal Region

Journal Article · Tue Sep 21 04:00:00 EDT 2010 · Structure

DOI:https://doi.org/10.1016/j.str.2009.08.002· OSTI ID:1006178

Kim, Mee Whi; Chelliah, Yogarany; Kim, Sang Woo; Otwinowski, Zbyszek; Bezprozvanny, Ilya

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.

• Research Organization: Argonne National Laboratory (ANL)
• Sponsoring Organization: USDOE
• OSTI ID: 1006178
• Journal Information: Structure, Journal Name: Structure Journal Issue: (9) ; 09, 2009 Vol. 17
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
99 GENERAL AND MISCELLANEOUS
CRYSTALLOGRAPHY
DISEASES
EXONS
FLEXIBILITY
GENETICS
PROTEINS