HSP90 at the hub of protein homeostasis: emerging mechanistic insights

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Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone that facilitates the maturation of a wide range of proteins (known as clients). Clients are enriched in signal transducers, including kinases and transcription factors. Therefore, HSP90 regulates diverse cellular functions and exerts marked effects on normal biology, disease and evolutionary processes. Recent structural and functional analyses have provided new insights on the transcriptional and biochemical regulation of HSP90 and the structural dynamics it uses to act on a diverse client repertoire. Comprehensive understanding of how HSP90 functions promises not only to provide new avenues for therapeutic intervention, but to shed light on fundamental biological questions.

Key Points

  • Heat shock protein 90 (HSP90) is an abundant and evolutionarily highly conserved molecular chaperone that regulates the maturation, activity and stability of a wide range of substrate proteins (clients). In eukaryotes, HSP90 is essential for survival during heat and other stresses, but it also has a central role in a vast array of signal transduction pathways in non-stressful conditions.

  • HSP90 exists as a dimer that undergoes ATP-dependent conformational changes during client protein maturation (known as the chaperone cycle). How the chaperone cycle is mechanistically connected to client protein folding is just beginning to be understood. The extreme conformation flexibility of HSP90 sets it apart from other chaperone systems and renders its study remarkably complex.

  • More than 20 known co-chaperones regulate HSP90 function in many different ways. Some co-chaperones modulate HSP90 ATPase activity and the chaperone cycle, and others seem to function as adaptors that recruit specific client proteins. Post-translational modifications of HSP90 and co-chaperones add further regulatory layers.

  • The best-characterized HSP90 client proteins are kinases and steroid hormone receptors. However, recent studies have uncovered numerous genes and proteins that either physically or genetically interact with HSP90. In yeast, Hsp90 is functionally linked to 20% of all genes. HSP90 has been implicated in RNA processing, membrane trafficking and in innate and adaptive immunity.

  • Despite the numerous client proteins, clear structural or sequence determinants for HSP90 binding remain largely unknown. Client protein recognition is one of the largest puzzles in the field.

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Figure 1: HSP90 domain structure and chaperone cycle.
Figure 2: Co-chaperones facilitate client maturation by interacting with distinct surfaces on HSP90.
Figure 3: HSP90 regulates diverse cellular processes through its interaction with client proteins.


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We thank C. McClellan, L. Pepper and L. Whitesell for helpful comments and suggestions. M.T. is supported by the Human Frontier Science Program long-term fellowship. D.F.J. is a Howard Hughes Medical Institute fellow of the Damon Runyon Cancer Research Foundation (DRG-1964-08). S.L. is an investigator of the Howard Hughes Medical Institute.

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Correspondence to Susan Lindquist.

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BioGRID database


Macromolecular crowding

The exclusion of the volume available for biochemical reactions in solutions with high concentrations of macromolecules. Crowding promotes intermolecular interactions.


The adoption of an inappropriate conformation or unfolded state and/or aggregation that can occur as a result of macromolecular crowding, environmental stress or mutation.


The homeostasis of a functional protein in the cell, which is a product of its concentration, conformation, interactions, localization and turnover.


A protein that assists in the folding of a protein or assembly of a complex but does not otherwise contribute to the final structure or function of the product.

Protein remodelling factor

A protein that remodels the structure and conformation of its target macromolecules, often in a manner that requires ATP hydrolysis.

Ubiquitin–proteasome system

A major mechanism of protein degradation in a cell. The covalent tagging of proteins with another small protein, ubiquitin, targets them for degradation by macromolecular assembly of the proteasome.

Heat shock protein

(HSP). A protein induced in response to increased temperature, classified according to its size. Many HSPs function as molecular chaperones.


A protein that associates with and promotes the function of chaperones by modulating their chaperoning activity and/or regulating their substrate specificity. The definition of a co-chaperone is somewhat arbitrary, as some co-chaperones have chaperoning activity even when they are not associated with the core chaperones.

X-ray crystallography

A method for determining the precise arrangement of atoms in a crystal, based on its diffraction pattern in an X-ray beam. This technique can be applied to protein crystals to obtain extremely high-resolution structures.

Electron microscopy

(EM). A form of microscopy that uses a particle beam of electrons to obtain high magnifications (up to 1,000,000-fold). Although EM generally provides lower resolution than other structural techniques, molecules can usually be visualized under closer to physiological conditions.

Hydrogen–deuterium (H–D) exchange

A reaction in which hydrogen atoms, typically backbone amides in the context of a protein, exchange with deuterium in a D2O-based buffer. The rate at which this exchange occurs is related to how solution-accessible each position is, and indicates whether a given residue is on the surface of the protein or more buried. Surface hydrogen atoms involved in hydrogen bonding interactions will not exchange.

Small nuclear RNP

A low molecular weight RNA, associated with proteins. Small nuclear RNPs mediate the splicing of primary RNA transcripts.


A family of proteins that are characterized by the presence of two homology domains: PAZ and PIWI. These proteins are essential for diverse RNA silencing pathways.

Molten globule

A partially denatured protein conformation with secondary structure similar to the native fold but without a fixed tertiary structure. Many proteins remain in such a state during folding or under partially denaturing conditions.

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