PolyQ expansion does not alter the Huntingtin-HAP40 complex

Huang, B.; Guo, Q.; Niedermeier, M. L.; Cheng, J.; Engler, T.; Maurer, M.; Pautsch, A.; Baumeister, W.; Stengel, F.; Kochanek, S.; Fernandez-Busnadiego, R.

doi:10.1101/2021.02.02.429316

bioRxiv · 10.1101/2021.02.02.429316

PolyQ expansion does not alter the Huntingtin-HAP40 complex

Huang, B.·Guo, Q.·Niedermeier, M. L.·Cheng, J.·Engler, T.·Maurer, M.·Pautsch, A.·Baumeister, W.·Stengel, F.·Kochanek, S.·Fernandez-Busnadiego, R.

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Abstract

The abnormal amplification of a CAG repeat in the gene coding for huntingtin (HTT) leads to Huntington disease (HD). At the protein level, this translates into the expansion of a poly-glutamine (polyQ) stretch located at the HTT N-terminus, which renders it 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 structure of HTT when associated with HAP40.

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Huang, B., Guo, Q., Niedermeier, M. L., Cheng, J., Engler, T., Maurer, M., Pautsch, A., Baumeister, W., Stengel, F., Kochanek, S., Fernandez-Busnadiego, R.. 2021-02-02. PolyQ expansion does not alter the Huntingtin-HAP40 complex. https://doi.org/10.1101/2021.02.02.429316

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