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DNAJB6 mutants display toxic gain of function through unregulated interaction with Hsp70 chaperones

Author

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  • Meital Abayev-Avraham

    (Weizmann Institute of Science)

  • Yehuda Salzberg

    (Weizmann Institute of Science)

  • Dar Gliksberg

    (Weizmann Institute of Science)

  • Meital Oren-Suissa

    (Weizmann Institute of Science)

  • Rina Rosenzweig

    (Weizmann Institute of Science)

Abstract

Molecular chaperones are essential cellular components that aid in protein folding and preventing the abnormal aggregation of disease-associated proteins. Mutations in one such chaperone, DNAJB6, were identified in patients with LGMDD1, a dominant autosomal disorder characterized by myofibrillar degeneration and accumulations of aggregated protein within myocytes. The molecular mechanisms through which such mutations cause this dysfunction, however, are not well understood. Here we employ a combination of solution NMR and biochemical assays to investigate the structural and functional changes in LGMDD1 mutants of DNAJB6. Surprisingly, we find that DNAJB6 disease mutants show no reduction in their aggregation-prevention activity in vitro, and instead differ structurally from the WT protein, affecting their interaction with Hsp70 chaperones. While WT DNAJB6 contains a helical element regulating its ability to bind and activate Hsp70, in LGMDD1 disease mutants this regulation is disrupted. These variants can thus recruit and hyperactivate Hsp70 chaperones in an unregulated manner, depleting Hsp70 levels in myocytes, and resulting in the disruption of proteostasis. Interfering with DNAJB6-Hsp70 binding, however, reverses the disease phenotype, suggesting future therapeutic avenues for LGMDD1.

Suggested Citation

  • Meital Abayev-Avraham & Yehuda Salzberg & Dar Gliksberg & Meital Oren-Suissa & Rina Rosenzweig, 2023. "DNAJB6 mutants display toxic gain of function through unregulated interaction with Hsp70 chaperones," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42735-z
    DOI: 10.1038/s41467-023-42735-z
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    1. Anne S. Wentink & Nadinath B. Nillegoda & Jennifer Feufel & Gabrielė Ubartaitė & Carolyn P. Schneider & Paolo De Los Rios & Janosch Hennig & Alessandro Barducci & Bernd Bukau, 2020. "Molecular dissection of amyloid disaggregation by human HSP70," Nature, Nature, vol. 587(7834), pages 483-488, November.
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    3. Melanie Meister-Broekema & Rebecca Freilich & Chandhuru Jagadeesan & Jennifer N. Rauch & Rocio Bengoechea & William W. Motley & E. F. Elsiena Kuiper & Melania Minoia & Gabriel V. Furtado & Maria A. W., 2018. "Myopathy associated BAG3 mutations lead to protein aggregation by stalling Hsp70 networks," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
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