Disease-Associated Polyglutamine Stretches in Monomeric Huntingtin Adopt a Compact Structure

JOURNAL OF MOLECULAR BIOLOGY

卷:421

Article

Peters-Libeu, Clare^1,2  Miller, Jason^1,3,4  Rutenber, Earl^1,2  Newhouse, Yvonne^1,2  Krishnan, Preethi^1,5  Cheung, Kenneth^1,5  Hatters, Danny^1,2  Brooks, Elizabeth^1,5  Widjaja, Kartika^1,5  Tina Tran^1,5  Mitra, Siddhartha^1,3,6  Arrasate, Montserrat^1,3  Mosquera, Luis A.⁷  Taylor, Dean⁸  Weisgraber, Karl H.^1,2,8  Finkbeiner, Steven^1,3,5,9,10 

[1] Gladstone Inst Neurol Dis, San Francisco, CA 94158 USA

[2] Gladstone Inst Cardiovasc Dis, San Francisco, CA 94158 USA

[3] Univ Calif San Francisco, Med Scientist Training Program, San Francisco, CA 94141 USA

[4] Univ Calif San Francisco, Chem & Chem Biol Program, San Francisco, CA 94141 USA

[5] Univ Calif San Francisco, Neurosci Program, San Francisco, CA 94141 USA

[6] Univ Calif San Francisco, Program Biomed Sci, San Francisco, CA 94141 USA

[7] Sunol Mol Corp, Miramar, FL 33025 USA

[8] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA

[9] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA

[10] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA

关键词: Huntington's disease;    huntingtin structure;    polyglutamine expansion;    amyloid;    antibody;   

DOI  :  10.1016/j.jmb.2012.01.034

来源: Elsevier

【 摘 要 】

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 angstrom resolution by X-ray crystallography. Modeling demonstrates that the paratope forms a groove suitable for binding two beta-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. (C) 2012 Elsevier Ltd. All rights reserved.

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