An exploration of the unanswered questions in how the molecular chaperone Hsp90 supports protein homeostasis, and how single-molecule techniques could drive future breakthroughs in answering them.

Chaperones ensure protein homeostasis and are conserved across species. The ATP-dependent chaperone Hsp90 is present from bacteria to eukaryotes, where it stabilizes and activates a wide range of subs...

Chaperones ensure protein homeostasis and are conserved across species. The ATP-dependent chaperone Hsp90 is present from bacteria to eukaryotes, wher…

Abstract. Protein homeostasis relies on chaperones such as HSP70 and HSP90, which assist in the folding, activation, and turnover of client proteins. Their

Leder et al. show that the chaperones PDIA6, Hsp70 BiP, ERdj3, PDIA1 and Hsp90 form co-condensates within the endoplasmic reticulum, enhancing folding and preventing misfolding of client proteins.

Hsp90 uses novel mechanisms in the regulation of proteostasis, chloroplast protection, phytohormone signaling, and immune defense to enhance plant adaptati

Tau aggregation, a hallmark of Alzheimer’s disease, disrupts neuron structure. Aging weakens chaperone defenses like Hsp90. This study designs β-Hsp90, a small peptide mimicking Hsp90, to prevent Tau aggregation, offering promise for new amyloid disease drugs.

Engler et al. define the Sgt1-specific domain as essential for the Sgt1 chaperone function in yeast. Through structural and biochemical analyses, they uncover unique interactions of Sgt1 with Hsp90 and client proteins that enhance client maturation efficiency. Sgt1 stabilizes Hsp90-client complexes by preventing their dissociation mediated by the co-chaperone Aha1.

Phosphorylation is a central post-translational mechanism for on-demand regulation of protein function. In the ATP-dependent molecular chaperone Hsp90, multiple phosphorylation sites have been implicated in activity control, yet how individual sites encode regulatory instructions remains unclear. Here, using solution NMR spectroscopy, we delineate how site-specific phosphorylation distinctly reshapes the conformational energy landscape of Hsp90 across its ATPase cycle. The phospho-mimetic mutation T115E induces a global redistribution of the N-terminal domain energy landscape, flattening conformational barriers, pre-populating a lid-closed-like excited state in the apo form, weakening ATP-driven stabilization, and impairing ADP-mediated resetting. In contrast, T36E preserves the overall structure but selectively rewires dynamics at the ATP-bound step, where accelerated exchange and a reduced excited-state population bias the ensemble toward the ground state. Together, these findings re

Post-translational modification (PTM) of proteins regulates cellular proteostasis by expanding protein functional diversity. This naturally leads to increased proteome complexity as the result of PTM ...