Secondary Structures of Native and Pathogenic Huntingtin N-Terminal Fragments

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• 作者：Maciej D艂ugosz ; Joanna Trylska
• 刊名：Journal of Physical Chemistry B
• 出版年：2011
• 出版时间：October 13, 2011
• 年：2011
• 卷：115
• 期：40
• 页码：11597-11608
• 全文大小：1208K
• 年卷期：v.115,no.40(October 13, 2011)
• ISSN：1520-5207

文摘

Huntington鈥檚 disease is a neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in the N-terminal fragment of the Huntingtin (Htt) protein. Structural properties of Htt N-terminal regions and the molecular mechanism leading to protein aggregation have not been fully explained yet. We performed all-atom replica exchange molecular dynamics to investigate the structures of Htt N-terminal parts with polyQ tracts of nonpathogenic and pathogenic lengths. The monomers were composed of the headpiece (17 N-terminal residues), a polyQ tract (polyQ₍₁₇₎ for native and polyQ₍₅₅₎ for pathogenic sequence), and a polyP₍₁₁₎ region, followed by 17 amino acids of mixed sequence. We found that corresponding regions in both fragments fold to similar secondary structures; the headpiece and polyQ stretch adopt mainly 伪-helical conformations, and polyP₍₁₁₎ forms the PP II-type helix. The native N-terminal fragment is more compact and stabilized by hydrophobic interactions between the surface of polyP₍₁₁₎ and the amphipathic helix of the headpiece. In the pathogenic fragment the headpiece is solvent exposed and does not interact with polyP₍₁₁₎. The predicted structure of the native N-terminal fragment agrees with the X-ray structure of the Htt first exon containing polyQ₍₁₇₎. The structure of the pathogenic fragment adheres to an aggregation model that is mediated by the Htt headpiece.