Disparate Mutations Confer Therapeutic Gain of Hsp104 Function.

  title={Disparate Mutations Confer Therapeutic Gain of Hsp104 Function.},
  author={Meredith E Jackrel and Keolamau Yee and Amber Tariq and Annie I. Chen and J. Shorter},
  journal={ACS chemical biology},
  volume={10 12},
  • Meredith E Jackrel, Keolamau Yee, +2 authors J. Shorter
  • Published 2015
  • Medicine, Biology
  • ACS chemical biology
  • Hsp104, a protein disaggregase from yeast, can be engineered and potentiated to counter TDP-43, FUS, or α-synuclein misfolding and toxicity implicated in neurodegenerative disease. Here, we reveal that extraordinarily disparate mutations potentiate Hsp104. Remarkably, diverse single missense mutations at 20 different positions interspersed throughout the middle domain (MD) and small domain of nucleotide-binding domain 1 (NBD1) confer a therapeutic gain of Hsp104 function. Moreover, potentiation… CONTINUE READING
    Potentiating Hsp104 activity via phosphomimetic mutations in the middle domain
    • 23
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    Therapeutic genetic variation revealed in diverse Hsp104 homologs
    • 1
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    Mining Disaggregase Sequence Space to Safely Counter TDP-43, FUS, and α-Synuclein Proteotoxicity
    • 11
    Mechanistic Insights into Hsp104 Potentiation*
    • 33
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    Engineering therapeutic protein disaggregases
    • 34
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    Engineering and Evolution of Molecular Chaperones and Protein Disaggregases with Enhanced Activity
    • 35
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    Publications referenced by this paper.
    Potentiated Hsp104 Variants Antagonize Diverse Proteotoxic Misfolding Events
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    Isolating potentiated Hsp104 variants using yeast proteinopathy models.
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    Hsp104: A Weapon to Combat Diverse Neurodegenerative Disorders
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