Epitopes described in "Disease-associated polyglutamine stretches in monomeric huntingtin adopt a compact structure."

Article Authors:Clare Peters-Libeu; Jason Miller; Earl Rutenber; Yvonne Newhouse; Preethi Krishnan; Kenneth Cheung; Danny Hatters; Elizabeth Brooks; Kartika Widjaja; Tina Tran; Siddhartha Mitra; Montserrat Arrasate; Luis A Mosquera; Dean Taylor; Karl H Weisgraber; Steven Finkbeiner
Article Title:Disease-associated polyglutamine stretches in monomeric huntingtin adopt a compact structure.
Reference Detail
Reference ID:1024586
Abstract:Abnormal polyglutamine (polyQ) tracts are the only common feature in nine proteins that each cause a dominant neurodegenerative disorder. In Huntington's disease, tracts longer than 36 glutamines in the protein huntingtin (htt) cause degeneration. In situ, monoclonal antibody 3B5H10 binds to different htt fragments in neurons in proportion to their toxicity. Here, we determined the structure of 3B5H10 Fab to 1.9 Å resolution by X-ray crystallography. Modeling demonstrates that the paratope forms a groove suitable for binding two -rich polyQ strands. Using small-angle X-ray scattering, we confirmed that the polyQ epitope recognized by 3B5H10 is a compact two-stranded hairpin within monomeric htt and is abundant in htt fragments unbound to antibody. Thus, disease-associated polyQ stretches preferentially adopt compact conformations. Since 3B5H10 binding predicts degeneration, this compact polyQ structure may be neurotoxic.
Affiliations:Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
Reference Type:Literature
PubMed ID:22306738
Journal:J Mol Biol
Journal Volume:421
Article Pages:587-600
Journal ISSN:0022-2836
Article Chemical List:Antibodies, Monoclonal;HTT protein, human;Immunoglobulin Fab Fragments;Nerve Tissue Proteins;Peptides;polyglutamine
Article MeSH List:Antibodies, Monoclonal(chemistry; metabolism); Crystallography, X-Ray; Humans; Huntington Disease(pathology); Immunoglobulin Fab Fragments(chemistry; metabolism); Models, Molecular; Nerve Tissue Proteins(chemistry; metabolism); Peptides(chemistry; metabolism); Protein Binding; Protein Conformation; Scattering, Small Angle
Curation Last Updated:2016-04-05 23:19:58