Monomeric Huntingtin Exon 1 Has Similar Overall Structural Features for Wild-Type and Pathological Polyglutamine Lengths
| Autor: | Kiersten M. Ruff, John B. Warner, Edward A. Lemke, Piau Siong Tan, Rohit V. Pappu, Hilal A. Lashuel |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Huntingtin Proline 010402 general chemistry 01 natural sciences Biochemistry Article Catalysis 03 medical and health sciences chemistry.chemical_compound Exon Colloid and Surface Chemistry Huntingtin Gene semi synthesis Fluorescence Resonance Energy Transfer single molecule FRET medicine Humans neurodegenerative diseases Huntingtin Protein Chemistry Neurodegeneration neurodegeneration Wild type Reproducibility of Results Exons General Chemistry Single-molecule FRET medicine.disease 0104 chemical sciences Crystallography Huntington Disease 030104 developmental biology Monomer Förster resonance energy transfer Biophysics Peptides polyglutamine atomistic simulations Huntington’s disease |
| Zdroj: | Journal of the American Chemical Society |
| ISSN: | 1520-5126 0002-7863 |
| DOI: | 10.1021/jacs.7b06659 |
| Popis: | Huntington’s disease is caused by expansion of a polyglutamine (polyQ) domain within exon 1 of the huntingtin gene (Httex1). A popular hypothesis is that the Httex1 protein undergoes sharp conformational changes as the polyQ length exceeds a threshold of 36 residues. 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 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 and this derives from increased prominence of the globular polyQ domain. More specifically, we show that that monomeric Httex1 adopts tadpole-like architectures for polyQ lengths above and beyond the pathological threshold. Additionally, our results suggest that higher order homo- and / or heterotypic interactions within distinct sub-populations of neurons are likely to be the main source of sharp polyQ length-dependencies of HD. These findings pave the way for uncovering the true structural basis of Httex1-mediated neurotoxicity. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|