期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 10, 页码 8188-8196出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.192013
关键词
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资金
- National Institutes of Health [R01NS053679, P01NS16375, 2NS45091, AG027936]
- DOE [DE-FG02-04ER25626]
- National Institutes of Health-NIGMS
- University of California at San Francisco Hillblom Center for the Biology of Aging
- Huntington Disease Society of America Coalition for the Cure
- CHDI, Inc.
Huntington disease results from an expanded polyglutamine region in the N terminus of the huntingtin protein. HD pathology is characterized by neuronal degeneration and protein inclusions containing N-terminal fragments of mutant huntingtin. Structural information is minimal, though it is believed that mutant huntingtin polyglutamine adopts beta structure upon conversion to a toxic form. To this end, we designed mammalian cell expression constructs encoding compact beta variants of Htt exon 1 N-terminal fragment and tested their ability to aggregate and induce toxicity in cultured neuronal cells. In parallel, we performed molecular dynamics simulations, which indicate that constructs with expanded polyglutamine beta-strands are stabilized by main-chain hydrogen bonding. Finally, we found a correlation between the reactivity to 3B5H10, an expanded polyglutamine antibody that recognizes a compact beta rich hairpin structure, and the ability to induce cell toxicity. These data are consistent with an important role for a compact beta structure in mutant huntingtin-induced cell toxicity.
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