The ability of Heat Shock Protein 90 (Hsp90) to hydrolyze ATP is essential for its chaperone function. The co-chaperone Aha1 stimulates Hsp90 ATPase activity, tailoring the chaperone function to specific "client" proteins. The intracellular signaling mechanisms directly regulating Aha1 association with Hsp90 remain unknown. Here, we show that c-Abl kinase phosphorylates Y223 in human Aha1 (hAha...

Heat shock protein 90 (hsp90) accounts for 1-2% of the total proteins in normal cells and it functions as a dimer. Hsp90 behaves as a molecular chaperone that folds, assembles, and stabilizes client proteins. We have developed a novel hsp90 inhibitor, and herein we describe the synthesis and biological activity of the dimerized variant of this inhibitor. Tethering a monomer inhibitor together p...

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Mutations in HSPB1 and HSPB8, members of the small heat shock protein family, have recently been shown to cause some distal motor neuropathies. Their function in motor neurones is now under scrutiny.

Cells may sense heat shock via the accumulation of thermally misfolded proteins. To explore this possibility, we determined the effect of protein misfolding on gene expression in the absence of temperature changes. The imino acid analog azetidine-2-carboxylic acid (AZC) is incorporated into protein competitively with proline and causes reduced thermal stability or misfolding. We found that addi...

A copper-(I)-catalyzed variation of the Huisgen 1,3-dipolar cycloaddition has been applied to lead the in living-cell mass-spectrometry based identification of protein targets of oleocanthal, a natural metabolite daily ingested by millions of people. Chemical proteomics revealed heat-shock proteins, HSP70 and HSP90, as main oleocanthal interactors in living systems. These two proteins are invol...

The aggregation of proteins inside cells is an organized process with cytoprotective function. In Saccharomyces cerevisiae, aggregating proteins are spatially sequestered to either juxtanuclear or peripheral sites, which target distinct quality control pathways for refolding and degradation. The cellular machinery driving the sequestration of misfolded proteins to these sites is unknown. In thi...

Small heat shock proteins (sHSPs) make up a class of molecular chaperones broadly observed across organisms. Many sHSPs form large oligomers that undergo dynamic subunit exchange that is thought to play a role in chaperone function. Though remarkably heterogeneous, sHSP oligomers share three types of intermolecular interactions that involve all three defined regions of a sHSP: the N-terminal re...