Secondary Structure of Huntingtin Amino-Terminal Region

Abstract

Summary Huntington's disease (HD) is a genetic neurodegenerative disorder resulting from polyglutamine (polyQ) expansion (> 36Q) within first exon of Huntingtin (Htt) protein. Here we applied X-ray crystallography to determine the secondary structure of the first exon (EX1) of Htt-17Q. The structure of Htt17Q-EX1 consists of an amino-terminal α-helix, a poly17Q region, and a polyproline helix formed by the proline-rich region. The poly17Q region adopts multiple conformations in the structure, including α-helix, random coil and extended loop. The conformation of the poly17Q region is influenced by the conformation of neighbouring protein regions, demonstrating 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.