Warner IV, John BlaineRuff, KierstenSiong Tan, PiauLemke, Edward A.Pappu, Rohit V.Lashuel, Hilal A.2017-09-222017-09-222017-09-22201710.1021/jacs.7b06659https://infoscience.epfl.ch/handle/20.500.14299/140797WOS:000413503300024Huntington’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.Huntington’s diseaseHuntingtinneurodegenerationneurodegenerative diseasessingle molecule FRETatomistic simulationspolyglutaminesemi synthesistext::journal::journal article::research article