Characterization of a possible amyloidogenic precursor in glutamine-repeat neurodegenerative diseases
AUTOR(ES)
Armen, Roger S.
FONTE
National Academy of Sciences
RESUMO
Several neurodegenerative diseases are linked to expanded repeats of glutamine residues, which lead to the formation of amyloid fibrils and neuronal death. The length of the repeats correlates with the onset of Huntington's disease, such that healthy individuals have <38 residues and individuals with >38 repeats exhibit symptoms. Because it is difficult to obtain atomic-resolution structural information for poly(l-glutamine) (polyQ) in aqueous solution experimentally, we performed molecular dynamics simulations to investigate the conformational behavior of this homopolymer. In simulations of 20-, 40-, and 80-mer polyQ, we observed the formation of the “α-extended chain” conformation, which is characterized by alternating residues in the αL and αR conformations to yield a sheet. The structural transition from disordered random-coil conformations to the α-extended chain conformation exhibits modest length and temperature dependence, in agreement with the experimental observation that aggregation depends on length and temperature. We propose that fibril formation in polyQ may occur through an α-sheet structure, which was proposed by Pauling and Corey [Pauling, L. & Corey, R. B. (1951) Proc. Natl. Acad. Sci. USA 37, 251-256]. Also, we propose an atomic-resolution model of how the inhibitory peptide QBP1 (polyQ-binding peptide 1) may bind to polyQ in an α-extended chain conformation to inhibit fibril formation.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1224618Documentos Relacionados
- Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases.
- Glutamine Repeats and Neurodegenerative Diseases: Molecular Aspects.
- Incorporation of glutamine repeats makes protein oligomerize: implications for neurodegenerative diseases.
- Animal models of neurodegenerative diseases
- Studying neurodegenerative diseases in culture models