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A Linear Lattice Model for Polyglutamine in CAG-Expansion Diseases
Melanie J. Bennett, Kathryn E. Huey-Tubman, Andrew B. Herr, Anthony P. West Jr., Scott A. Ross and Pamela J. Bjorkman
Proceedings of the National Academy of Sciences of the United States of America
Vol. 99, No. 18 (Sep. 3, 2002), pp. 11634-11639
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/3073091
Page Count: 6
You can always find the topics here!Topics: Exons, Proteins, Ligands, Modeling, Molecules, Disease models, Biosensing techniques, Pathology, Antibodies, Huntington disease
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Huntington's disease and several other neurological diseases are caused by expanded polyglutamine [poly(Gln)] tracts in different proteins. Mechanisms for expanded (>36 Gln residues) poly(Gln) toxicity include the formation of aggregates that recruit and sequester essential cellular proteins [Preisinger, E., Jordan, B. M., Kazantsev, A. & Housman, D. (1999) Phil. Trans. R. Soc. London B 354, 1029-1034; Chen, S., Berthelier, V., Yang, W. & Wetzel, R. (2001) J. Mol. Biol. 311, 173-182] and functional alterations, such as improper interactions with other proteins [Cummings, C. J. & Zoghbi, H. Y. (2000) Hum. Mol. Genet. 9, 909-916]. Expansion above the "pathologic threshold" (≈36 Gln) has been proposed to induce a conformational transition in poly(Gln) tracts, which has been suggested as a target for therapeutic intervention. Here we show that structural analyses of soluble huntingtin exon 1 fusion proteins with 16 to 46 glutamine residues reveal extended structures with random coil characteristics and no evidence for a global conformational change above 36 glutamines. An antibody (MW1) Fab fragment, which recognizes full-length huntingtin in mouse brain sections, binds specifically to exon 1 constructs containing normal and expanded poly(Gln) tracts, with affinity and stoichiometry that increase with poly(Gln) length. These data support a "linear lattice" model for poly(Gln), in which expanded poly(Gln) tracts have an increased number of ligand-binding sites as compared with normal poly(Gln). The linear lattice model provides a rationale for pathogenicity of expanded poly(Gln) tracts and a structural framework for drug design.
Proceedings of the National Academy of Sciences of the United States of America © 2002 National Academy of Sciences