J. Shorter

Design principles to tailor Hsp104 therapeutics

This paper identifies design principles for modifying Hsp104 to enhance its therapeutic potential by tuning its collaboration with Hsp70 and Hsp40.

Defining a small-molecule stimulator of the human Hsp70-disaggregase system with selectivity for DnaJB proteins

The paper identifies a small-molecule stimulator of the human Hsp70-disaggregase system that selectively activates DnaJB1- or DnaJB4-containing chaperone complexes.

Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains

The paper identifies short RNAs that prevent and reverse pathological fibrillization of RNA-binding proteins like FUS and TDP-43, showing therapeutic potential for ALS/FTD.

Molecular determinants of Karyopherin-β2 chaperone and disaggregation activity

This study identifies the minimal functional domain of Kapβ2 required for preventing and reversing prion-like domain-mediated aggregation of disease-linked RNA-binding proteins.

Unique structural features govern the activity of a human mitochondrial AAA+ disaggregase, Skd3.

The paper reports the structure of Skd3-substrate complex, revealing its dodecamer formation and mechanism of protein disaggregation, with implications for SCN and MGCA7.

Tuning Hsp104 specificity to selectively detoxify alpha-synuclein

The paper engineers Hsp104 variants with substrate specificity to selectively reduce alpha-synuclein toxicity in a Parkinson's disease model.

Therapeutic genetic variation revealed in diverse Hsp104 homologs

The paper identifies therapeutic genetic variations in Hsp104 homologs that specifically counter proteotoxicity in yeast, human cells, and C. elegans by enhancing passive chaperone activity.

Skd3 (human CLPB) is a potent mitochondrial protein disaggregase that is inactivated by 3-methylglutaconic aciduria-linked mutations

This study identifies Skd3 (human CLPB) as a mitochondrial protein disaggregase inactivated by mutations causing 3-methylglutaconic aciduria.

Conformational Plasticity of the ClpAP AAA+ Protease Couples Protein Unfolding and Proteolysis

This study determines high-resolution structures of E. coli ClpAP complex in substrate-bound states to elucidate the mechanism of protein unfolding and proteolysis coupling.

Structural basis for substrate gripping and translocation by the ClpB AAA+ disaggregase

The paper determines the cryo-EM structure of a hyperactive ClpB variant bound to casein and ATPγS to elucidate its substrate gripping and translocation mechanism.