Monomeric huntingtin exon 1 has similar overall structural features for wild type and pathological polyglutamine lengths

• Verfasst von: Warner, John B. [VerfasserIn]
• Verfasst von: Lemke, Edward A. [VerfasserIn]
• Titel: Monomeric huntingtin exon 1 has similar overall structural features for wild type and pathological polyglutamine lengths
• Verf.angabe: John B. Warner, Kiersten M. Ruff, Piau Siong Tan, Edward A. Lemke, Rohit V. Pappu, and Hilal A. Lashuel
• Umfang: 14 S.
• Fussnoten: Gesehen am 26.09.2018
• Titel Quelle: Enthalten in: American Chemical Society: Journal of the American Chemical Society
• Jahr Quelle: 2017
• Band/Heft Quelle: 139(2017), 41, S. 14456-14469
• ISSN Quelle: 1520-5126
• DOI: doi:10.1021/jacs.7b06659
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1581315724

Abstract

, Huntington’s disease is caused by expansion of a polyglutamine (polyQ) domain within exon 1 of the huntingtin gene (Httex1). The prevailing hypothesis is that the monomeric Httex1 protein undergoes sharp conformational changes as the polyQ length exceeds a threshold of 36-37 residues. Here, we test this hypothesis by combining novel semi-synthesis strategies with state-of-the-art single-molecule Förster resonance energy transfer measurements on biologically relevant, monomeric Httex1 proteins of five different polyQ lengths. Our results, integrated with atomistic simulations, negate the hypothesis of a sharp, polyQ length-dependent change in the structure of monomeric Httex1. Instead, they support a continuous global compaction with increasing polyQ length that derives from increased prominence of the globular polyQ domain. Importantly, we show that monomeric Httex1 adopts tadpole-like architectures for polyQ lengths below and above the pathological threshold. Our results suggest that higher order homotypic and/or heterotypic interactions within distinct sub-populations of neurons, which are inevitable at finite cellular concentrations, are likely to be the main source of sharp polyQ length dependencies of HD.