Journal article
Tadpole-like Conformations of Huntingtin Exon 1 Are Characterized by Conformational Heterogeneity that Persists regardless of Polyglutamine Length
EA Newcombe, KM Ruff, A Sethi, AR Ormsby, YM Ramdzan, A Fox, AW Purcell, PR Gooley, RV Pappu, DM Hatters
Journal of Molecular Biology | ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD | Published : 2018
Abstract
Soluble huntingtin exon 1 (Httex1) with expanded polyglutamine (polyQ) engenders neurotoxicity in Huntington's disease. To uncover the physical basis of this toxicity, we performed structural studies of soluble Httex1 for wild-type and mutant polyQ lengths. Nuclear magnetic resonance experiments show evidence for conformational rigidity across the polyQ region. In contrast, hydrogen–deuterium exchange shows absence of backbone amide protection, suggesting negligible persistence of hydrogen bonds. The seemingly conflicting results are explained by all-atom simulations, which show that Httex1 adopts tadpole-like structures with a globular head encompassing the N-terminal amphipathic and polyQ ..
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Awarded by National Institutes of Health
Funding Acknowledgements
The US National Institutes of Health supported this work through Grant 5R01NS056114 to R.V.P. We thank Oded Kleifeld from the Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, for technical assistance with the proteomics work (now at Faculty of Biology, Technion-lsrael Institute of Technology, Haifa 3200003). This work builds on a prior collaboration with John Warner IV, Piau Siong Tan, Edward Lemke, and Hilal Lashuel that yielded atomistic descriptions of Httexl monomers using smFRET and computer simulations [22]. We (K.M. R. and R.V.P) are grateful to Drs. Warner, Lemke, and Lashuel for their assistance and for their insights regarding the conformational ensembles of Httex1.