Modulation of the Hsp90 Chaperone Cycle by a Stringent Client Protein

Lorenz, Oliver R.; Freiburger, Lee; Rutz, Daniel; Krause, Maike; Zierer, Bettina K.; Alvira, Sara; Cuéllar, Jorge; Valpuesta, José M.; Madl, Tobias; Sattler, Michael; Büchner, Johannes

doi:10.1016/j.molcel.2014.02.003

Cited by 132 publications

(217 citation statements)

References 66 publications

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“…The C-terminal part of Cdc37 interacts only with the kinase, whereas the N-terminal domain is bound to Hsp90 but can simultaneously interfere with the nucleotide binding pocket of the kinase. It still remains an open question how a client is attached to Hsp90, in particular as binding sites in the N-terminal, middle, and C-terminal domains of Hsp90 have been shown to be important for client interactions (9,25,49). Given the ample number of binding sites between Cdc37 and kinase and between Cdc37 and Hsp90, it certainly argues for a closely assembled and regulated protein complex participating in the maturation of protein kinases.…”

Section: Discussionmentioning

confidence: 99%

“…The molecular chaperone Hsp90 4 itself is a dimeric protein consisting of three domains: an N-terminal ATP binding domain; a middle domain, which is supposed to be involved in client binding; and a C-terminal dimerization domain (24,25). ATP binding leads to a rearrangement of the three domains from an open V-shaped conformation to a closed conformation (5,26,27).…”

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confidence: 99%

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Hsp90·Cdc37 Complexes with Protein Kinases Form Cooperatively with Multiple Distinct Interaction Sites

Eckl

Scherr

Freiburger

et al. 2015

Journal of Biological Chemistry

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Protein kinases are the most prominent group of heat shock protein 90 (Hsp90) clients and are recruited to the molecular chaperone by the kinase-specific cochaperone cell division cycle 37 (Cdc37). The interaction between Hsp90 and nematode Cdc37 is mediated by binding of the Hsp90 middle domain to an N-terminal region of Caenorhabditis elegans Cdc37 (CeCdc37). Here we map the binding site by NMR spectroscopy and define amino acids relevant for the interaction between CeCdc37 and the middle domain of Hsp90. Apart from these distinct Cdc37/ Hsp90 interfaces, binding of the B-Raf protein kinase to the cochaperone is conserved between mammals and nematodes. In both cases, the C-terminal part of Cdc37 is relevant for kinase binding, whereas the N-terminal domain displaces the nucleotide from the kinase. This interaction leads to a cooperative formation of the ternary complex of Cdc37 and kinase with Hsp90. For the mitogen-activated protein kinase extracellular signalregulated kinase 2 (Erk2), we observe that certain features of the interaction with Cdc37⅐Hsp90 are conserved, but the contribution of Cdc37 domains varies slightly, implying that different kinases may utilize distinct variations of this binding mode to interact with the Hsp90 chaperone machinery.The human genome encodes up to 500 kinases, which represent one of the largest families of genes in eukaryotes (1, 2). They regulate essential intracellular processes like proliferation, differentiation, development, stress response, and apoptosis. All protein kinases share a conserved catalytic domain, which switches between an active and an inactive state (3,4). A large number of these protein kinases are dependent on the Hsp90 chaperone system, which modulates their maturation and prevents their degradation (5-8). So far only little structural information of the chaperone-kinase complex is available (9). To facilitate kinase processing by the Hsp90 chaperone machinery, the specific cochaperone Cdc37 is required (9 -11).A well described function of this cochaperone is to slow down the ATPase activity of Hsp90 (12). It is widely expected that Hsp90 and its partner protein Cdc37 bind to the catalytic domain of the kinase (13-16). It remains elusive how the ternary complex consisting of protein kinase, Hsp90 and Cdc37 is structurally organized and how the protein kinase is processed by the chaperone system. Recently Cdc37 was observed to compete with nucleotide binding to the kinase domain of B-Raf (17), but the role of Hsp90 in these structures remains enigmatic. Although Hsp90 is essential for ligand binding in case of steroid hormone receptors the role for B-Raf activation is rather unclear (18). B-Raf is mutated in many human cancers and is known to form complexes with Hsp90 and Cdc37 in cell free systems (19). The interaction with the kinase is also weakened in vivo in presence of an anticancer drug that disrupts nucleotide binding to Hsp90 (20). Given the recent evolution of Hsp90 as a potential cancer target (21-23), it is important to clarify the mechanis...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Hsp90·Cdc37 Complexes with Protein Kinases Form Cooperatively with Multiple Distinct Interaction Sites

Eckl

Scherr

Freiburger

et al. 2015

Journal of Biological Chemistry

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“…These differences in substrate binding mode may be modulated by the ionic strength, as discussed by Didenko et al [190]. On the Hsp90 side, it was established that the Hsp90 dynamics are decelerated upon substrate binding [180,181,191]. The most accurate description of a substrate interaction with Hsp90 until now is the complex structure of Hsp90 and Tau, which revealed an extended binding interface with a multitude of binding sites to prevent aggregation of Tau [192].…”

Section: Hsp90mentioning

confidence: 97%

“…All three domains have been implicated in being involved in substrate binding, but direct data for Hsp90-C are fewer than for the other domains [181]. Hsp90 shows a high degree of structural variability, with dramatic nucleotide-dependent conformational rearrangements alternating between open and closed conformations [182,183].…”

Section: Hsp90mentioning

confidence: 99%

Chaperones and chaperone–substrate complexes: Dynamic playgrounds for NMR spectroscopists

Burmann¹,

Hiller²

2015

Progress in Nuclear Magnetic Resonance Spectroscopy

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“…The middle domain (M-domain) is involved in client binding (7,8), and the N-terminal domain binds ATP. Upon ATP binding, the N-terminal domains dimerize, leading to the closed state (9)(10)(11)(12)(13), whereas the open state is regained upon ATP-hydrolysis (14).…”

mentioning

confidence: 99%

Conformational processing of oncogenic v-Src kinase by the molecular chaperone Hsp90

Boczek

Reefschläger

Dehling

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Hsp90 is a molecular chaperone involved in the activation of numerous client proteins, including many kinases. The most stringent kinase client is the oncogenic kinase v-Src. To elucidate how Hsp90 chaperones kinases, we reconstituted v-Src kinase chaperoning in vitro and show that its activation is ATP-dependent, with the cochaperone Cdc37 increasing the efficiency. Consistent with in vivo results, we find that Hsp90 does not influence the almost identical c-Src kinase. To explain these findings, we designed Src kinase chimeras that gradually transform c-Src into v-Src and show that their Hsp90 dependence correlates with compactness and folding cooperativity. Molecular dynamics simulations and hydrogen/deuterium exchange of Hsp90-dependent Src kinase variants further reveal increased transitions between inactive and active states and exposure of specific kinase regions. Thus, Hsp90 shifts an ensemble of conformations of v-Src toward high activity states that would otherwise be metastable and poorly populated.Cdc37 | kinase activation | metastable states | conformational ensembles | chaperone mechanism

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Modulation of the Hsp90 Chaperone Cycle by a Stringent Client Protein

Cited by 132 publications

References 66 publications

Hsp90·Cdc37 Complexes with Protein Kinases Form Cooperatively with Multiple Distinct Interaction Sites

Hsp90·Cdc37 Complexes with Protein Kinases Form Cooperatively with Multiple Distinct Interaction Sites

Chaperones and chaperone–substrate complexes: Dynamic playgrounds for NMR spectroscopists

Conformational processing of oncogenic v-Src kinase by the molecular chaperone Hsp90

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