Mining Disaggregase Sequence Space to Safely Counter TDP-43, FUS, and α-Synuclein Proteotoxicity

Amber Tariq, Jia Bei Lin, Meredith E. Jackrel, Christina D. Hesketh, Peter J. Carman, Korrie L. Mack, Rachel Weitzman, Craig Gambogi, Oscar A. Hernandez Murillo, Elizabeth A. Sweeny, Esin Gurpinar, Adam L. Yokom, Stephanie N. Gates, Keolamau Yee, Saurabh Sudesh, Jacob Stillman, Alexandra N. Rizo, Daniel R. Southworth, James Shorter

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Hsp104 is an AAA+ protein disaggregase, which can be potentiated via diverse mutations in its autoregulatory middle domain (MD) to mitigate toxic misfolding of TDP-43, FUS, and α-synuclein implicated in fatal neurodegenerative disorders. Problematically, potentiated MD variants can exhibit off-target toxicity. Here, we mine disaggregase sequence space to safely enhance Hsp104 activity via single mutations in nucleotide-binding domain 1 (NBD1) or NBD2. Like MD variants, NBD variants counter TDP-43, FUS, and α-synuclein toxicity and exhibit elevated ATPase and disaggregase activity. Unlike MD variants, non-toxic NBD1 and NBD2 variants emerge that rescue TDP-43, FUS, and α-synuclein toxicity. Potentiating substitutions alter NBD1 residues that contact ATP, ATP-binding residues, or the MD. Mutating the NBD2 protomer interface can also safely ameliorate Hsp104. Thus, we disambiguate allosteric regulation of Hsp104 by several tunable structural contacts, which can be engineered to spawn enhanced therapeutic disaggregases with minimal off-target toxicity.

Original languageEnglish (US)
Pages (from-to)2080-2095.e6
JournalCell Reports
Issue number8
StatePublished - Aug 20 2019

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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