4.7 Review

Advances towards Understanding the Mechanism of Action of the Hsp90 Complex

Related references

Note: Only part of the references are listed.
Article Multidisciplinary Sciences

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Summary: Maintaining a healthy proteome is crucial for the survival of all organisms. Hsp90 and Hsp70 are essential molecular chaperones that assist in the folding, remodelling, and maturation of numerous client proteins. The cryo-electron microscopy structure of the GR-loading complex has uncovered the molecular basis of direct coordination by Hsp90 and Hsp70, providing insights into the mechanism of client protein chaperoning.

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Summary: The study reveals the cryo-electron microscopy structure of human GR-maturation complex (GR-Hsp90-p23), showing that the GR ligand-binding domain is restored to folded, ligand-bound conformation and threaded through the Hsp90 lumen, with p23 directly stabilizing native GR through a C-terminal helix, enhancing ligand binding. This client bound to Hsp90 structure contrasts with the unfolded kinase-Hsp90 structure, indicating that Hsp90 can dictate client-specific folding outcomes through direct co-chaperone-client interactions.

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Summary: The authors describe a new technique that combines two-color fluorescence microscopy with photoinduced electron transfer probes to simultaneously detect two structural coordinates in single protein molecules. They demonstrate this technique by observing three critical structural changes within the Hsp90 molecular chaperone machinery, revealing synchronicity of conformational motions and evidence for a cooperativity mechanism in the chaperone's catalytic cycle. Single-molecule PET fluorescence microscopy opens up new avenues for exploring protein dynamics and allosteric mechanisms in multiple dimensions.

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Aha1 Exhibits Distinctive Dynamics Behavior and Chaperone-Like Activity

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Summary: Aha1 is a unique co-chaperone that enhances the ATPase activity of Hsp90 and exhibits chaperoning activity against stress-denatured proteins. The N-terminal domain of Aha1 is in an energy-unfavorable state in solution, promoting its interaction with partner proteins like Hsp90's middle domain.

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Summary: The Hsp90 chaperone facilitates the folding and activation of hundreds of client proteins in the cell, with FKBP51 serving as a catalytic co-chaperone during the folding process. The cryo-EM structure of the human Hsp90:FKBP51:p23 complex revealed the key interactions between cochaperones and Hsp90 during client maturation.

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Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex

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Co-chaperone regulation of conformational switching in the Hsp90 ATPase cycle

G Siligardi et al.

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Activation of the ATPase activity of Hsp90 by the stress-regulated cochaperone Aha1

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Regulation of Hsp90 ATPase activity by the co-chaperone Cdc37p/p50cdc97

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HSP40 binding is the first step in the HSP90 chaperoning pathway for the progesterone receptor

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Stimulation of the weak ATPase activity of human Hsp90 by a client protein

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Coordinated ATP hydrolysis by the Hsp90 dimer

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Assembly of τ protein into Alzheimer paired helical filaments depends on a local sequence motif (306VQIVYK311) forming β structure

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