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.
The circadian clock in mammals is driven by an autoregulatory transcriptional feedback mechanism that takes about 24 hours to complete. A key component of this mechanism is a heterodimeric transcriptional activator consisting of two bHLH-PAS domain protein subunits, CLOCK and BMAL1. Here we report the crystal structure of a complex containing the mouse CLOCK:BMAL1 bHLH-PAS domains at 2.3Å resolution. The structure reveals an unusual asymmetric heterodimer with the three domains in each of the two subunits, bHLH, PAS-A and PAS-B tightly intertwined and involved in dimerization interactions, resulting in three distinct protein interfaces. Mutations that perturb the observed heterodimer interfaces affect the stability and activity of the CLOCK:BMAL1 complex as well as the periodicity of the circadian oscillator. The structure of the CLOCK:BMAL1 complex is a starting point for understanding at an atomic level the mechanism driving the mammalian circadian clock.
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