The Predicted Structure of the Headpiece of the Huntingtin Protein and Its Implications on Huntingtin Aggregation

Biophysics Program, Stanford University, Stanford, CA 94305, USA.
Journal of Molecular Biology (Impact Factor: 4.33). 02/2009; 388(5):919-27. DOI: 10.1016/j.jmb.2009.01.032
Source: PubMed

ABSTRACT We have performed simulated tempering molecular dynamics simulations to study the thermodynamics of the headpiece of the Huntingtin (Htt) protein (N17(Htt)). With converged sampling, we found this peptide is highly helical, as previously proposed. Interestingly, this peptide is also found to adopt two different and seemingly stable states. The region from residue 4 (L) to residue 9 (K) has a strong helicity from our simulations, which is supported by experimental studies. However, contrary to what was initially proposed, we have found that simulations predict the most populated state as a two-helix bundle rather than a single straight helix, although a significant percentage of structures do still adopt a single linear helix. The fact that Htt aggregation is nucleation dependent infers the importance of a critical transition. It has been shown that N17(Htt) is involved in this rate-limiting step. In this study, we propose two possible mechanisms for this nucleating event stemming from the transition between two-helix bundle state and single-helix state for N17(Htt) and the experimentally observed interactions between the N17(Htt) and polyQ domains. More strikingly, an extensive hydrophobic surface area is found to be exposed to solvent in the dominant monomeric state of N17(Htt). We propose the most fundamental role played by N17(Htt) would be initializing the dimerization and pulling the polyQ chains into adequate spatial proximity for the nucleation event to proceed.

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Available from: Stephen Tam, Jan 09, 2015
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    • "Since N17 was demonstrated to be involved in the rate-limiting step for the formation of the initial aggregation nucleus, two possible mechanisms for the nucleating event were proposed in this study. These are based on a transition between the two-helix and singlehelix state of N17 and on the interactions between the N17 and the polyQ tract (Kelley et al. 2009). Moreover, a recent Monte Carlo simulation study, along with circular dichroism experiments, described the effect of N17 on polyQ conformations and intermolecular interactions. "
    Huntington's Disease - Core Concepts and Current Advances, 02/2012; , ISBN: 978-953-307-953-0
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    • "The Htt Nterminal headpiece modulates subcellular localization and aggregation of Htt exp (Atwal et al., 2007; Rockabrand et al., 2007; Thakur et al., 2009), and definitive information about its secondary structure is useful for understanding these effects. The N-terminal region of Htt is α-helical in all our crystals (Fig 3), consistent with the molecular dynamics simulations and biophysical measurements (Atwal et al., 2007; Kelley et al., 2009). The agreement with these studies indicate that ability to form α-helix is an intrinsic property of Htt aminoterminal region and not a result of crystallization of Htt17Q-EX1 as amino-terminal MBPfusion protein. "
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    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.
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