[NMR paper] Structure and Dynamics of the Huntingtin Exon-1 N-Terminus: A*Solution NMR Perspective.

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Structure and Dynamics of the Huntingtin Exon-1 N-Terminus: A*Solution NMR Perspective.

Related Articles Structure and Dynamics of the Huntingtin Exon-1 N-Terminus: A*Solution NMR Perspective.

J Am Chem Soc. 2017 Jan 13;:

Authors: Baias M, Smith PE, Shen K, Joachimiak LA, ?erko S, Ko?mi?ski W, Frydman J, Frydman L


Abstract
Many neurodegenerative diseases are characterized by misfolding and aggregation of an expanded polyglutamine tract (polyQ). Huntington's Disease, caused by expansion of the polyQ tract in exon 1 of the Huntingtin protein (Htt), is associated with aggregation and neuronal toxicity. Despite recent structural progress in understanding the structures of amyloid fibrils, little is known about the solution states of Htt in general, and about molecular details of their transition from soluble to aggregation-prone conformations in particular. This is an important question, given the increasing realization that toxicity may reside in soluble conformers. This study presents an approach that combines NMR with computational methods to elucidate the structural conformations of Htt Exon 1 in solution. Of particular focus was Htt's N17 domain sited N-terminal to the polyQ tract, which is key to enhancing aggregation and modulate Htt toxicity. Such in-depth structural study of Htt presents a number of unique challenges: the long homopolymeric polyQ tract contains nearly identical residues, exon 1 displays a high degree of conformational flexibility leading to a scaling of the NMR chemical shift dispersion, and a large portion of the backbone amide groups are solvent-exposed leading to fast hydrogen exchange and causing extensive line broadening. To deal with these problems, NMR assignment was achieved on a minimal Htt exon 1, comprising the N17 domain, a polyQ tract of 17 glutamines, and a short hexameric polyProline region that does not contribute to the spectrum. A pH titration method enhanced this polypeptide's solubility and, with the aid of