J. E. Gestwicki

De novo designed Hsp70 activator dissolves intracellular condensates

The paper designs Hsp70 activators that dissolve intracellular condensates by modulating Hsp70 ATPase activity and promoting protein refolding.

Phosphorylation of a Cleaved Tau Proteoform at a Single Residue Inhibits Binding to the E3 Ubiquitin Ligase, CHIP

This study identifies phosphorylation at residue S416 on tauC3 as a mechanism that inhibits its degradation by CHIP, contributing to its accumulation in Alzheimer's disease.

Interaction with the membrane-anchored protein CHIC2 constrains the ubiquitin ligase activity of CHIP

This study identifies CHIC2 as a chaperone-independent regulator of CHIP, showing it attenuates CHIP's ubiquitin ligase activity and contributes to neurodegeneration in C. elegans.

CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis

The paper uses CRISPR screens in iPSC-derived neurons to identify factors controlling tau aggregation, finding new pathways and potential therapeutic targets for tauopathies.

Asymmetric apical domain states of mitochondrial Hsp60 coordinate substrate engagement and chaperonin assembly

The paper determines cryo-EM structures of a mtHsp60 mutant to show how apical domains coordinate client engagement and chaperonin assembly during the ATP-dependent cycle.

Conformationally responsive dyes enable protein-adaptive Differential Scanning Fluorometry

This paper introduces paDSF, a protein-adaptive Differential Scanning Fluorometry method that improves compatibility with proteins and expands observable processes.

An unbiased screen identified the Hsp70-BAG3 complex as a regulator of myosin binding protein C3 stability.

A high-throughput compound screen identified JG98 and parthenolide as reducing MyBP-C levels, revealing the Hsp70-BAG3 complex as a regulator of MyBP-C stability in HCM.

The Chemical Features of Polyanions Modulate Tau Aggregation and Conformational States

This study investigates how different polyanions affect tau aggregation and conformation, finding that valency and identity influence aggregation kinetics and fibril morphology.

Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 Macrodomain of SARS-CoV-2

The paper computationally designs and experimentally validates potent inhibitors of the SARS-CoV-2 Nsp3 Macrodomain, identifying 160 ligands and 152 crystal structures with submicromolar affinity.

Two distinct classes of co-chaperones compete for the EEVD motif in heat shock protein 70 (Hsp70) to tune its activity

The paper identifies two co-chaperones that compete for the EEVD motif of Hsp70, influencing its activity by determining whether bound proteins are folded or degraded.

PIKfyve inhibition blocks endolysosomal escape of α-synuclein fibrils and spread of α-synuclein aggregation

The paper identifies PIKfyve inhibition as a strategy to block α-synuclein fibril escape from lysosomes, reducing aggregation spread in a human cell model.

Allosteric HSP70 inhibitors perturb mitochondrial proteostasis and overcome proteasome inhibitor resistance in multiple myeloma

This study identifies allosteric HSP70 inhibitors that overcome proteasome inhibitor resistance in multiple myeloma by targeting mitochondrial HSPA9 and disrupting mitoribosome stability.

Three Essential Resources to Improve Differential Scanning Fluorimetry (DSF) Experiments

The paper provides three resources to improve DSF experiments: an interactive theoretical framework, practical tips, and online data analysis tools, available at DSFworld.

Compromised function of the ESCRT pathway promotes endolysosomal escape of tau seeds and propagation of tau aggregation

The paper identifies ESCRT pathway components as regulators of tau aggregation propagation by enabling endolysosomal escape of tau seeds.

Management of Hsp90-Dependent Protein Folding by Small Molecule Targeting the Aha1 Co-Chaperone

This study identifies SEW04784, a small molecule that disrupts Aha1-stimulated Hsp90 ATPase activity, showing therapeutic potential in prostate cancer and tauopathies without affecting basal Hsp90 function.