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TitlePathological polyQ expansion does not alter the conformation of the Huntingtin-HAP40 complex.
Journal, issue, pagesStructure, Vol. 29, Issue 8, Page 804-809.e5, Year 2021
Publish dateAug 5, 2021
AuthorsBin Huang / Qiang Guo / Marie L Niedermeier / Jingdong Cheng / Tatjana Engler / Melanie Maurer / Alexander Pautsch / Wolfgang Baumeister / Florian Stengel / Stefan Kochanek / Rubén Fernández-Busnadiego /
PubMed AbstractThe 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 ...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.
External linksStructure / PubMed:33909994
MethodsEM (single particle)
Resolution3.6 - 4.1 Å
Structure data

EMDB-30911, PDB-7dxj:
Human 46QHuntingtin-HAP40 complex structure
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-30912, PDB-7dxk:
Human 128QHuntingtin-HAP40 complex structure
Method: EM (single particle) / Resolution: 4.1 Å

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsSTRUCTURAL PROTEIN / Huntingtin / 46Q / HAP40 / 128Q

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