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Mining Disaggregase Sequence Space to Safely Counter TDP-43, FUS, and α-Synuclein Proteotoxicity. Cell Rep 2019 Aug 20;28(8):2080-2095.e6

Date

08/23/2019

Pubmed ID

31433984

Pubmed Central ID

PMC6750954

DOI

10.1016/j.celrep.2019.07.069

Scopus ID

2-s2.0-85070688471 (requires institutional sign-in at Scopus site)   27 Citations

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.

Author List

Tariq A, Lin J, Jackrel ME, Hesketh CD, Carman PJ, Mack KL, Weitzman R, Gambogi C, Hernandez Murillo OA, Sweeny EA, Gurpinar E, Yokom AL, Gates SN, Yee K, Sudesh S, Stillman J, Rizo AN, Southworth DR, Shorter J

Author

Elizabeth Sweeny PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adenosine Triphosphate
Amino Acid Sequence
Azetidinecarboxylic Acid
DNA-Binding Proteins
Heat-Shock Proteins
Mutant Proteins
Mutation, Missense
Protein Aggregates
Protein Domains
RNA-Binding Protein FUS
Saccharomyces cerevisiae
Saccharomyces cerevisiae Proteins
Temperature
alpha-Synuclein