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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 ?-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.

SUBMITTER: Jackrel ME

PROVIDER: S-EPMC4684741 | biostudies-other | 2015 Dec

REPOSITORIES: biostudies-other

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Disparate Mutations Confer Therapeutic Gain of Hsp104 Function.

Jackrel Meredith E ME Yee Keolamau K Tariq Amber A Chen Annie I AI Shorter James J

ACS chemical biology 20151015 12

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 ...[more]

PMID: 26441009

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