Huntington disease is an autosomal-dominant neurodegenerative disorder caused by
a polyglutamine (polyQ) expansion (> 35Q) in the first exon (EX1) of
huntingtin protein (Htt). mHtt protein is thought to adopt one or more toxic
conformation(s) that are involved in pathogenic interactions in cells . However,
the structure of mHtt is not known. Here, we present a near atomic resolution
structure of mHtt36Q-EX1. To facilitate crystallization, three histidine
residues (3H) were introduced within the Htt36Q stretch resulting in the
sequence of Q 7HQHQHQ 27. The Htt36Q3H region adopts α-helix, loop, β-hairpin
conformations. Furthermore, we observed interactions between the backbone of the
Htt36Q3H β-strand with the aromatic residues mimicking putative-toxic
interactions with other proteins. Our findings support previous predictions that
the expanded mHtt-polyQ region adopts a β-sheet structure. Detailed structural
information about mHtt improves our understanding of the pathogenic mechanisms
in HD and other polyQ expansion disorders and may form the basis for rational
design of small molecules that target toxic conformations of disease-causing
proteins.
