Proteins are the active workforce in the cell. Among them, chaperone proteins are responsible for maintaining proteostasis, i.e., sustaining a functional proteome adapted to ever-changing cellular and environmental conditions. In eukaryotic cells, the heat shock protein 90 (Hsp90) plays a central role in proteostasis, as it provides a scaffold that binds substrate proteins (termed clients) as well as a variety of helper chaperones (known as cochaperones) (Picard, 2022; Noddings et al., 2021; Wang et al., 2021; Verba et al., 2016; Lee et al., 2021; Wen et al., 2023; Oberoi et al., 2022; García-Alonso et al., 2022). Hsp90 can therefore be regarded as a versatile workbench (Oberoi et al., 2022) where cochaperones act as tools to customise the chaperone’s function as needed for client recruitment (Wegele et al., 2006; Biebl et al., 2022; Taipale et al., 2012), (re)folding (Pirkl and Buchner, 2001; Riggs et al., 2007), (de)activation (Broemer et al., 2004; Belova et al., 2008), degradation (Dickey et al., 2007), or protection from degradation (Oberoi et al., 2022). Due to the many clients relying on its function, Hsp90 constitutes a proteostatic hub in eukaryotes (Taipale et al., 2012; Biebl et al., 2020), while only a handful of prokaryotic Hsp90 clients are known (Wickner et al., 2021). Among the hundreds of eukaryotic clients are transcription factors, signalling kinases, DNA replication proteins, cell division regulators, synapse proteins, and many more (Picard, 2022). Hsp90 is highly conserved throughout prokaryotes to higher eukaryotes (Chen et al., 2006), and appears to have back-transferred from eukaryotes to their archaeal precursors through horizontal gene transfer (Rebeaud et al., 2021). In the absence of stress, Hsp90 constitutes 1–2% of the protein mass in eukaryotic cells (Lai et al., 1984) and exists in super-stoichiometric ratios (∼2:1) to its cochaperones while it is outcompeted tenfold in concentration by that of all of its clients (Finka and Goloubinoff, 2013). Under stress conditions, Hsp90 expression is strongly upregulated (Borkovich et al., 1989). The active Hsp90 dimer (Wayne and Bolon, 2007) proceeds through an intricate functional cycle involving ATP hydrolysis, multiple conformational rearrangements, and (transient) protein-protein interactions, whose functional roles have remained largely enigmatic despite over 40 years of Hsp90 research (Ritossa, 1962; Finkelstein and Strausberg, 1983). This is surprising for an ATPase as prevalent as Hsp90, and clearly sets Hsp90 apart from many other important ATPases with very well-understood molecular mechanisms. In this Review, we highlight the most important ‘known unknowns’ of Hsp90’s molecular function, with the goal of inspiring new routes to address them and advance the field (Figure 1).

Figure 1

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Structurally, Hsp90 monomers consist of three domains (Figure 2A): an N-terminal domain (NTD), a middle domain (MD), and a carboxy-terminal domain (CTD), as well as an unstructured charged linker region between the NTD and MD. The NTD contains an ATP-binding pocket and a flexible loop segment, the so-called lid, which can fold over the ATP pocket (Prodromou et al., 2000; Schulze et al., 2016; Henot et al., 2022). The charged linker modulates Hsp90 function via NTD interactions (Hainzl et al., 2009; Jahn et al., 2014) and can influence client binding (López et al., 2021). Most known client binding sites are located in the MD (Noddings et al., 2021; Wang et al., 2021; Verba et al., 2016; Oberoi et al., 2022; García-Alonso et al., 2022; Lorenz et al., 2014; Radli and Rüdiger, 2018), while specific MD residues also participate in nucleotide binding, alongside NTD residues (Mader et al., 2020). The CTD provides the main dimerisation interface (Minami et al., 1994), and can participate in client interactions (Verba et al., 2016; Lorenz et al., 2014). In cytosolic eukaryotic Hsp90, the CTD contains an additional recognition motif (MEEVD) (Biebl and Buchner, 2019) for tetratricopeptide repeat-containing cochaperones, such as Sti1/Hop and Cpr6 (Schopf et al., 2017). The Hsp90 dimer undergoes large conformational rearrangements, involving conformational ensembles with several open (V-shaped), intermediate, and compacted dimer structures (Schopf et al., 2017; Ali et al., 2006; Shiau et al., 2006; Mickler et al., 2009; Ratzke et al., 2012b), as illustrated in Figure 1 (grey shading). Hsp90 is also assisted by cochaperones that either directly modify clients, or interact with Hsp90 to modulate client processing (Röhl et al., 2013), resulting in a vast variety of transiently occurring chaperone complexes. Post-translational modifications (PTMs) provide an additional level of regulation of Hsp90 function and we refer the reader to a recent comprehensive review of PTMs on Hsp90 (Backe et al., 2020). For example, specific PTMs alter Hsp90’s ATPase activity (Backe et al., 2023), exert allosteric effects (Rehn et al., 2016; Zuehlke et al., 2017), may confer client specificity to Hps90 (Scroggins et al., 2007), target Hsp90 for degradation (Mollapour et al., 2010), and regulate its interaction with clients (Backe et al., 2023; Zuehlke et al., 2017; Scroggins et al., 2007; Rani et al., 2024; Xu et al., 2012; Duval et al., 2007; Burmann et al., 2020), cochaperones (Mollapour et al., 2010; Xu et al., 2012; Vaughan et al., 2008; Bachman et al., 2018; Mollapour et al., 2014), and small-molecule inhibitors (Mollapour et al., 2014; Beebe et al., 2013). Further increasing the complexity is asymmetry in the Hsp90 dimer and its interactions (Mayer and Le Breton, 2015). Examples include the individual ATP hydrolysis by Hsp90 monomers within a dimer (Mishra and Bolon, 2014; Huang et al., 2019; D’Annessa et al., 2021; Wolf et al., 2021; Elnatan et al., 2017), asymmetric binding of cochaperones to the Hsp90 dimer (Noddings et al., 2021; Wang et al., 2021; Verba et al., 2016; Lee et al., 2021; Wen et al., 2023; Oberoi et al., 2022; García-Alonso et al., 2022; Retzlaff et al., 2010), asymmetric PTMs of the Hsp90 dimer (Mollapour et al., 2014), asymmetric client binding (Finci et al., 2024), and the increase of Hsp90 dimer ATPase activity through asymmetry in N-terminal β-strap dynamics (Magnan et al., 2024). Given this polymorphic behaviour, it has been impossible to define a single functional cycle for Hsp90, which – alongside other peculiarities discussed below – limits the current understanding of the Hsp90 functional mechanism.

Figure 2

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Client processing by Hsp90

Client processing by Hsp90_euk can be classified into refolding (Kirschke et al., 2014; Morán Luengo et al., 2018), holding (Freeman and Morimoto, 1996), sorting for degradation (Dickey et al., 2007; Karagöz et al., 2014; Falsone et al., 2009), ligand binding regulation (Kirschke et al., 2014; Pratt and Dittmar, 1998; Ghosh and Stuehr, 2012), re-/de-activation (Broemer et al., 2004; Belova et al., 2008; Mu et al., 2023; Sato et al., 2000), and regulation of assemblies (Zhao et al., 2008; Manjarrez et al., 2014). Hsp90’s diverse clients differ both structurally and functionally (Taipale et al., 2012; Pearl and Prodromou, 2006; McClellan et al., 2007) and, related to that, Hsp90 does not have a well-defined client binding site, which is in contrast to other chaperones, such as Hsp70. Instead, Hsp90 clients form numerous low-affinity contacts through hydrophobic interactions (Babu and Freeman, 2024) and some client-specific charge-charge interactions (Radli and Rüdiger, 2018). Certain clients (e.g. GR and kinases) primarily bind to Hsp90’s lumen formed by both MDs, while intrinsically disordered proteins (IDPs, e.g. Tau, misfolded transthyretin, etc.) bind interfaces extending from the MD to the NTD (Oroz et al., 2017; Rutledge et al., 2022). Despite the breadth of clients, Hsp90 is understood to exhibit client-specific chaperoning action, presumably through specific sets of cochaperones (Noddings et al., 2021; Wang et al., 2021; Verba et al., 2016; Lee et al., 2021; Wen et al., 2023; Oberoi et al., 2022; Liu et al., 2020). Indeed, only certain cochaperones function as integral components of the Hsp90_euk system, while others are client-specific and provide Hsp90 with the necessary plasticity (Sahasrabudhe et al., 2017; Radli and Rüdiger, 2017; Figure 3a), e.g., through specific client recruitment (Taipale et al., 2012) or by modulating the time for which a client is bound to Hsp90 (Biebl et al., 2020; Wang et al., 2006; Sahasrabudhe et al., 2017; Prince and Neckers, 2011; Koulov et al., 2010).

Figure 3

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Exciting molecular-level details of client processing have recently been revealed for the GR, Hop/Sti, p23 system in 3D structures of these multi-component complexes, solved by the Agard lab (Noddings et al., 2021; Wang et al., 2021) with cryo-EM. They represent two snapshots along the complex client processing trajectory, termed the loading complex (Wang et al., 2021) and the maturation complex (Noddings et al., 2021). Together, they suggest a sliding or ratcheting movement of the client GR through the Hsp90 lumen. Likewise, three kinase clients (BRAF_V600E [Oberoi et al., 2022], Cdk4 [Verba et al., 2016], RAF1 [García-Alonso et al., 2022; Finci et al., 2024]) and the aryl hydrocarbon receptor (Wen et al., 2023) also thread through the Hsp90 lumen. Such molecular clamping by Hsp90 was suggested to keep the domains of multidomain clients separated, thus facilitating their independent folding (Noddings et al., 2021) and preventing inter-domain misfolding (Figure 3b). Destabilised kinases are thought to be held by Hsp90 to facilitate their reactivation (Verba and Agard, 2017), after local kinase motions poise the kinase for Hsp90 processing (Keramisanou et al., 2022). During the processing of Tau, which binds to open Hsp90_euk in numerous conformations (Karagöz et al., 2014), Hsp90 has been hypothesised to act as a holdase, preventing the formation of toxic oligomeric species (Rutledge et al., 2022). However, the precise role of Hsp90 in Tau aggregation is still a topic of ongoing research, as discussed in a recent review (Ramirez and Zweckstetter, 2023). For example, it was also found that Hsp90 recruits CHIP resulting in the ubiquitination and degradation of Tau (Dickey et al., 2007). For the p53 DBD, smFRET measurements revealed considerable dynamics in the presence of all relevant (co-)chaperones, suggesting that p53 conformation is constantly remodelled by Hsp70/Hsp90 (Dahiya et al., 2019). Overall, Hsp90’s structural plasticity allows clients and cochaperones to individually orchestrate client-processing mechanisms, making it a flexible master chaperone.

The energetic driving forces for Hsp90’s diverse molecular modes of action – folding, holding, stretching, etc. – result from different underlying kinetics of inter- and intra-molecular interactions. For example, the balance between client holding versus folding depends on the (forward and reverse) kinetic rate constants of the two processes: if the client-folding step is slower than client (re-)binding to the chaperone, the holdase function is kinetically favoured and folding is rate-limiting for that particular client (Kawagoe et al., 2022). The sequential refolding of individual structural elements of the client can decrease their local affinity for Hsp90, enabling gradual dissociation from Hsp90. This process allows clients to sample a wide range of conformations prior to dissociating from Hsp90 (Qu et al., 2024). Transient interactions are prerequisite for this dynamic model. Thermodynamically, transient interactions can result in avidity effects where multiple low-affinity contacts add up, resulting in high affinities with down to nanomolar dissociation constants (K_d) (Nooren and Thornton, 2003). While such strong avidity is characterised by large interfaces (∼1500 Å) (Noddings et al., 2023; Nooren and Thornton, 2003), the low affinities of Hsp90 to its clients (micromolar K_d) (Lorenz et al., 2014; Karagöz et al., 2014) likely result from much smaller interfaces.

For folding processes to occur, specific energy barriers need to be overcome. While small conformational changes have low energy barriers and occur spontaneously in thermal equilibrium, large rearrangements with higher energy barriers are not accessible by thermal energy alone (1 k_BT≈ 4.1×10⁻²¹ J ≙ 0.6 kcal/mol). In other words, although folding is an exothermic process (cf. Anfinsen’s dogma [Anfinsen, 1973]), energy barriers can kinetically trap un- or misfolded states and external energy is often required for efficient folding. This can be binding energy from molecular interactions (including cochaperone binding), ATP hydrolysis energy, or potential energy changes provided by covalent PTMs. Notably, for its client-specific function, Hsp90 exploits all of these modes of action in one unified system, and first efforts have been made to directly quantify the energies involved (Mashaghi et al., 2022). Overall, Hsp90_euk has emerged as a highly multi-functional workbench that uses cochaperones as tools for the customised processing of its diverse clients. Many proposed models for client processing are yet to be experimentally proven. New routes to address this using single-molecule approaches are discussed below and in Box 1.

The timing of Hsp90’s functional cycle

The precise temporal progression through Hsp90’s functional cycle is a matter of ongoing research (Figure 4), complicated (amongst others) by Hsp90’s client-specific behaviour, leading to many different functional cycles proposed in the literature (Verba et al., 2016; Lee et al., 2021; Wen et al., 2023; Kirschke et al., 2014). We focus here on two of the best-studied systems, the Hsp70-Hsp90 cascade and the kinase cycle, which both progress through three main phases: (i) client loading/recruitment, leading to (ii) client processing and maturation, followed by (iii) client release. Both examples show cochaperone-dependent client loading, but we note that several clients bind Hsp90 without cochaperone involvement, e.g., the IDPs Tau (Karagöz et al., 2014) and α-synuclein (Daturpalli et al., 2013). Also, due to the generally transient low-affinity interactions, numerous intermediate complexes and their interconversion kinetics are yet to be revealed and quantified. Therefore, as direct real-time observations are still lacking, the depicted cycles represent early models from which neither a strict order of events nor their timing can be inferred.

Figure 4

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The Hsp70-Hsp90 cascade (Figure 4a) was found to process the transcription factors GR (Noddings et al., 2021; Wang et al., 2021; Kirschke et al., 2014; Morán Luengo et al., 2018) and p53 (Dahiya et al., 2019), as well as Argonaute which regulates transcription through RNA silencing (Tsuboyama et al., 2018; Pare et al., 2009; Pare et al., 2013; Wang et al., 2013). Clients are prepared for Hsp90 interaction through active (partial) unfolding by Hsp70 via hydrophobic interactions (Rüdiger et al., 1997), a mechanism supported by findings of single-molecule optical tweezer experiments (Dahiya et al., 2022; Moessmer et al., 2022). Two recently resolved multipartite intermediate states, the loading (Wang et al., 2021) and the maturation complex (Noddings et al., 2021), provide much awaited molecular-level structural details. The loading complex, Hsp70-Bridge-Client-Hsp90, contains a ‘bridging’ protein (e.g. Hop [Morán Luengo et al., 2018], NudC [Biebl et al., 2022], Tomm34 [Trcka et al., 2014]) that facilitates client transfer from Hsp70 to Hsp90. Interestingly, Hop was found not to be required in vivo (Bhattacharya et al., 2020) which may reflect redundancy among bridging proteins. Another bridging protein, NudC was found to directly recruit Hsp40-bound clients to Hsp90 (Biebl et al., 2022). Following recruitment, the partially unfolded client is clamped within the closed Hsp90 dimer lumen, and whether this is a directional or reversible step still needs to be determined by time-resolved techniques. Next, the Hsp90-client-p23 maturation complex (Noddings et al., 2021) is formed after dissociation of the bridging protein and Hsp70, where dissociation involves either nucleotide exchange or Hsp90 ATPase activity (Kirschke et al., 2014). p23 binds and stabilises Hsp90’s closed state (Richter et al., 2004) during GR processing, while it is not required for luciferase processing (Morán Luengo et al., 2018). Interestingly, an smFRET study reported directionality of an Hsp90/p23 system conferred by ATP binding and hydrolysis even in the absence of a client protein (Ratzke et al., 2014), implying that cochaperones can steer the Hsp90 cycle. Additionally, p23 binding was found to relieve a Hop-inhibited Hsp70-Hsp40-Hop-GRLBD-Hsp90 complex and maximise GR hormone binding recovery beyond the levels achieved by the binding of either Hop or p23 alone (Dahiya et al., 2022), further indicating cochaperone-endowed directionality in the Hsp70-Hsp90 cascade. Other cochaperones may further modulate client-specific regulation, as was shown for immunophilins in the context of GR (Lee et al., 2021; Noddings et al., 2023). Further, cochaperones themselves can be regulated by PTMs (e.g. Hop phosphorylation at residue Y354 reducing its binding to Hsp70/90 [Castelli et al., 2023]). The position of GR captured in the Hsp90 lumen shifts by several amino acids between the 3D-resolved loading and the maturation states, implying a sliding or ratcheting movement (Noddings et al., 2021). Although not all molecular details are known yet (e.g. on client release), the Hsp70-Hsp90 cascade appears to enable client activation through assisted folding (Kirschke et al., 2014; Morán Luengo et al., 2018).

Another functional cycle has been described for kinase-specific processing (Verba et al., 2016; Taipale et al., 2012; Figure 4b). Here, Cdc37 plays the client-recruiting role, where the loading complex consists of Cdc37-Client-Hsp90. Cdc37 stabilises a partially unfolded kinase state (Keramisanou et al., 2022; Keramisanou et al., 2016), in which the kinase N and C domains are separated (Verba et al., 2016), and thereby primes the kinase client for subsequent interaction with residues in the Hsp90 dimer lumen (Verba and Agard, 2017). Cdc37 can bind Hsp90 in its open state, inhibiting Hsp90’s ATPase through interaction with its ATP lid (Roe et al., 2004). In this loading complex, phosphorylation of serine 13 on Cdc37 (Cdc37-pSer13) by casein kinase 2 (Miyata and Nishida, 2004) is critical for kinase activation by Hsp90 (Miyata and Nishida, 2004; Shao et al., 2003), and stabilises the kinase-bound conformation (Verba et al., 2016). The maturation complex is obtained by binding of protein phosphatase 5 (Pp5), whereafter Pp5 dephosphorylates the kinase clients (Oberoi et al., 2022) as well as Cdc37-pSer13 (Vaughan et al., 2008; Oberoi et al., 2016). Steric hindrance in a cryo-EM structure of Hsp90-Cdc37-CRaf-PP5 suggests kinase dissociation prior to Cdc37 dephosphorylation and dissociation (Jaime-Garza et al., 2023). As Cdc37’s pSer13 residue is buried in the closed, ATP-bound Hsp90 dimer (Oberoi et al., 2022), the Pp5 dephosphorylation of Cdc37 likely happens upon Hsp90 transitioning from a compact ATP-bound state to a post-hydrolysis state, which is more flexible than the former (Graf et al., 2009). The Hsp90-Cdc37-kinase system has been described to process clients by ‘factory resetting’ of phosphorylations (Oberoi et al., 2022), as well as physical stabilisation or shielding of clients (Verba and Agard, 2017). Next to client PTMs, Hsp90 and Cdc37 are understood to undergo a series of modifications during the general kinase client cycle, which are suggested to provide directionality to the functional cycle (Xu et al., 2012). Another possible route of conferral of directionality, in addition to PTMs, is by cochaperones and ATP binding or hydrolysis, as revealed for the Hsp90-Cdc37-kinase cycle by smFRET, evaluated through direct observation of Hps90 open/closed dynamics (Ratzke et al., 2014; Vollmar et al., 2024). Most notably this was found for a complete reaction mixture, which included Hsp90, ATP, Cdc37, Sba1 (p23), Aha1, as well as the client kinase Ste11.

The timing of functional cycles is known to be crucial for biomolecular systems and their precise regulation. Prominent examples include: the pausing mechanism of RNA polymerase (Lerner et al., 2016; Janissen et al., 2022), ribosome rotation, stalling, and frameshifting during translation (Tsai et al., 2016), processive protein threading by proteases (Cordova et al., 2014), etc. For Hsp90, this level of mechanistic understanding has not yet been reached. Up to now, only some of the state transitions of the functional cycle could be observed experimentally, leaving a range of questions unanswered: When and for what is ATP binding required? When does ATP hydrolysis take place? Is ATP binding or hydrolysis or rather cochaperone phosphorylation dominant in providing directionality – and hence processivity – to a given Hsp90 cycle? In cellulo, do cochaperones interact with and dissociate from Hsp90 in a given sequence or randomly? What determines which client processing mechanism is employed? What is the timing of specific state transitions during client processing? Clearly, the time-resolved direct observation of Hsp90’s functional cycles would hold tremendous information about cycle timing, off-target waiting states, the client-specific differences, and the energetic driving forces of Hsp90’s functional cycle.

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Author details

1. Laura-Marie Silbermann

   Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, Netherlands

   Contribution

   Conceptualization, Visualization, Writing – original draft, Writing – review and editing

   Contributed equally with

   Benjamin Vermeer

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5989-1774

2. Benjamin Vermeer

   Laboratory of Biophysics, Wageningen University & Research, Wageningen, Netherlands

   Present address

   Biomolecular Nano-Dynamics Lab, Department of Chemistry, University of Basel, Basel, Switzerland

   Contribution

   Conceptualization, Visualization, Writing – original draft, Writing – review and editing

   Contributed equally with

   Laura-Marie Silbermann

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8375-2966

3. Sonja Schmid

   Laboratory of Biophysics, Wageningen University & Research, Wageningen, Netherlands

   Present address

   Biomolecular Nano-Dynamics Lab, Department of Chemistry, University of Basel, Basel, Switzerland

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Project administration, Writing – review and editing

   For correspondence

   sonja.schmid@unibas.ch

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3710-5602

4. Katarzyna Tych

   Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, Netherlands

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Visualization, Project administration, Writing – review and editing

   For correspondence

   k.m.tych@rug.nl

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-9091-0507

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