A5023862821- Genetics, Aging, and Longevity in Model Organisms
- Endoplasmic Reticulum Stress and Disease
- Heat shock proteins research
- Amyotrophic Lateral Sclerosis Research
- Fungal and yeast genetics research
University of Pennsylvania
2019
Hsp104 is a hexameric AAA + ATPase and protein disaggregase found in yeast, which can be potentiated via mutations its middle domain (MD) to counter toxic phase separation by TDP-43, FUS α-synuclein connected devastating neurodegenerative disorders. Subtle missense the MD enhance activity, indicating that post-translational modification of specific residues might also potentiate Hsp104. Indeed, several serine threonine throughout phosphorylated vivo. Here, we introduce phosphomimetic...
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 fatal neurodegenerative disorders. Problematically, MD variants exhibit off-target toxicity. Here, we mine disaggregase sequence space safely enhance activity single nucleotide-binding 1 (NBD1) or NBD2. Like variants, NBD counter toxicity elevated ATPase activity. Unlike non-toxic NBD1 NBD2...