Pathological polyQ expansion does not alter the conformation of the 
Huntingtin-HAP40 complex

Huang, Bin; Guo, Qiang; Niedermeier, Marie L.; Cheng, Jingdong; Engler, Tatjana; Maurer, Melanie; Pautsch, Alexander; Baumeister, Wolfgang; Stengel, Florian; Kochanek, Stefan; Fernandez-Busnadiego, Ruben

doi:10.1016/j.str.2021.04.003

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Pathological polyQ expansion does not alter the conformation of the Huntingtin-HAP40 complex

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Guo, Qiang
Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society;

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Baumeister, Wolfgang
Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society;

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Fernandez-Busnadiego, Ruben
Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Huang, B., Guo, Q., Niedermeier, M. L., Cheng, J., Engler, T., Maurer, M., et al. (2021). Pathological polyQ expansion does not alter the conformation of the Huntingtin-HAP40 complex. Structure, 29(8), 804-809. doi:10.1016/j.str.2021.04.003.

Cite as: https://hdl.handle.net/21.11116/0000-0009-2CEA-F

Abstract

The abnormal amplification of a CAG repeat in the gene coding for huntingtin (HTT) leads to Huntington's disease (HD). At the protein level, this translates into the expansion of a polyglutamine (polyQ) stretch located at the HTT N terminus, which renders HTT aggregation prone by unknown mechanisms. Here we investigated the effects of polyQ expansion on HTT in a complex with its stabilizing interaction partner huntingtin-associated protein 40 (HAP40). Surprisingly, our comprehensive biophysical, crosslinking mass spectrometry and cryo-EM experiments revealed no major differences in the conformation of HTT-HAP40 complexes of various polyQ length, including 17QHTT-HAP40 (wild type), 46QHTT-HAP40 (typical polyQ length in HD patients), and 128QHTT-HAP40 (extreme polyQ length). Thus, HTT polyQ expansion does not alter the global conformation of HTT when associated with HAP40.