title: Disparate Mutations Confer Therapeutic Gain of Hsp104 Function.
abstract: 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 emerges from deletion of MD helix 3 or 4 or via synergistic missense mutations in the MD distal loop and helix 4. We define the most critical aspect of Hsp104 potentiation as enhanced disaggregase activity in the absence of Hsp70 and Hsp40. We suggest that potentiation likely stems from a loss of a fragilely constrained autoinhibited state that enables precise spatiotemporal regulation of disaggregase activity.
authors.affiliation: Department of Biochemistry and Biophysics, ‡Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Meredith E
authors.initials: ME
authors.lastname: Jackrel
authors.affiliation: Department of Biochemistry and Biophysics, ‡Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Keolamau
authors.initials: K
authors.lastname: Yee
authors.affiliation: Department of Biochemistry and Biophysics, ‡Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Amber
authors.initials: A
authors.lastname: Tariq
authors.affiliation: Department of Biochemistry and Biophysics, ‡Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Annie I
authors.initials: AI
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Biophysics, ‡Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: James
authors.initials: J
authors.lastname: Shorter
mesh_terms: D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008958:Models, Molecular; D020125:Mutation, Missense; D019636:Neurodegenerative Diseases / Q000628:therapy*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D017510:Protein Folding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D006360:Heat-Shock Proteins; D018696:Neuroprotective Agents; D029701:Saccharomyces cerevisiae Proteins; C070972:HsP104 protein, S cerevisiae