Disparate Mutations Confer Therapeutic Gain of Hsp104 Function

Meredith E. Jackrel, Keolamau Yee, Amber Tariq, Annie I. Chen, James Shorter

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2672-2679
Number of pages8
JournalACS chemical biology
Volume10
Issue number12
DOIs
StatePublished - Oct 5 2015

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine

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