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

Amber Tariq, JiaBei 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. Cell Reports 2019 Read More

Abstract

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. Tariq et al. disambiguate the allosteric regulation of Hsp104 by several tunable structural contacts, which can be engineered to spawn enhanced therapeutic disaggregases with minimal off-target toxicity. Non-toxic nucleotide-binding domain 1 (NBD1) and NBD2 variants emerge that rescue TDP-43, FUS, and α-synuclein toxicity connected to neurodegenerative disease. © 2019 The Author(s)

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Posted on August 27, 2019
Posted in: HPAN, Neurodegeneration, Publications Authors: