title: Solid-State Nuclear Magnetic Resonance on the Static and Dynamic Domains of Huntingtin Exon-1 Fibrils.
abstract: Amyloid-like fibrils formed by huntingtin exon-1 (htt_ex1) are a hallmark of Huntington's disease (HD). The structure of these fibrils is unknown, and determining their structure is an important step toward understanding the misfolding processes that cause HD. In HD, a polyglutamine (polyQ) domain in htt_ex1 is expanded to a degree that it gains the ability to form aggregates comprising the core of the resulting fibrils. Despite the simplicity of this polyQ sequence, the structure of htt_ex1 fibrils has been difficult to determine. This study provides a detailed structural investigation of fibrils formed by htt_ex1 using solid-state nuclear magnetic resonance (NMR) spectroscopy. We show that the polyQ domain of htt_ex1 forms the static amyloid core similar to polyQ model peptides. The Gln residues of this domain exist in two distinct conformations that are found in separate domains or monomers but are relatively close in space. The rest of htt_ex1 is relatively dynamic on an NMR time scale, especially the proline-rich C-terminus, which we found to be in a polyproline II helical and random coil conformation. We observed a similar dynamic C-terminus in a soluble form of htt_ex1, indicating that the conformation of this part of htt_ex1 is not changed upon its aggregation into an amyloid fibril. From these data, we propose a bottlebrush model for the fibrils formed by htt_ex1. In this model, the polyQ domains form the center and the proline-rich domains the bristles of the bottlebrush.
authors.affiliation: Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, 1501 San Pablo Street, Los Angeles, California 90033, United States.
authors.forename: J Mario
authors.initials: JM
authors.lastname: Isas
authors.affiliation: Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, 1501 San Pablo Street, Los Angeles, California 90033, United States.
authors.forename: Ralf
authors.initials: R
authors.lastname: Langen
authors.affiliation: Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, 1501 San Pablo Street, Los Angeles, California 90033, United States.
authors.forename: Ansgar B
authors.initials: AB
authors.lastname: Siemer
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D005091:Exons; D006801:Humans; D000071058:Huntingtin Protein; D009682:Magnetic Resonance Spectroscopy; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D066329:Protein Aggregates; D017510:Protein Folding; D017434:Protein Structure, Tertiary
chemical_list: D000682:Amyloid; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D010455:Peptides; D066329:Protein Aggregates; C011083:polyproline; C097188:polyglutamine