Physical Interaction between Bacterial Heat Shock Protein (Hsp) 90 and Hsp70 Chaperones Mediates Their Cooperative Action to Refold Denatured Proteins

Nakamoto, Hitoshi; Fujita, Kensaku; Ohtaki, Aguru; Watanabe, Satoru; Narumi, Shoichi; Maruyama, Takahiro; Suenaga, Emi; Misono, Tomoko; Kumar, Penmetcha K. R.; Goloubinoff, Pierre; Yoshikawa, Hideki

doi:10.1074/jbc.m113.524801

Cited by 65 publications

(59 citation statements)

References 37 publications

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“…In addition to ATP, TRAP1-dependent protein folding also requires the functional cooperation of the mitochondrial Hsp70 system. The latter supports a direct physical interaction, as was recently reported for cytosolic Hsp90 chaperones (5)(6)(7)50), and opens up new avenues for drug development by targeting the specific interaction between mitochondrial chaperones.…”

Section: Discussionmentioning

confidence: 81%

Mitochondrial Hsp90 is a ligand-activated molecular chaperone coupling ATP binding to dimer closure through a coiled-coil intermediate

Sung

Lee

Kim

et al. 2016

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

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Heat-shock protein of 90 kDa (Hsp90) is an essential molecular chaperone that adopts different 3D structures associated with distinct nucleotide states: a wide-open, V-shaped dimer in the apo state and a twisted, N-terminally closed dimer with ATP. Although the N domain is known to mediate ATP binding, how Hsp90 senses the bound nucleotide and facilitates dimer closure remains unclear. Here we present atomic structures of human mitochondrial Hsp90 N (TRAP1 N ) and a composite model of intact TRAP1 revealing a previously unobserved coiled-coil dimer conformation that may precede dimer closure and is conserved in intact TRAP1 in solution. Our structure suggests that TRAP1 normally exists in an autoinhibited state with the ATP lid bound to the nucleotide-binding pocket. ATP binding displaces the ATP lid that signals the cis-bound ATP status to the neighboring subunit in a highly cooperative manner compatible with the coiled-coil intermediate state. We propose that TRAP1 is a ligand-activated molecular chaperone, which couples ATP binding to dramatic changes in local structure required for protein folding.TRAP1 | Hsp90 | molecular chaperone H eat-shock protein of 90 kDa (Hsp90) is a conserved ATPdependent molecular chaperone (1-4), which together with heat-shock protein of 70 kDa (Hsp70) (5-7) and a cohort of cochaperones (8-10), promotes the late-stage folding of Hsp90 client proteins (11). It is presumed that almost 400 different proteins, including a majority of signaling and tumor promoting proteins, depend on cytosolic Hsp90 for folding (12). Consequently, the ability to inactivate multiple oncogenic pathways simultaneously has made Hsp90 a major target for drug development (13), with several Hsp90 inhibitors currently undergoing clinical trials (14).Hsp90 chaperones display conformational plasticity in solution (2, 15, 16), with different adenine nucleotides either facilitating or stabilizing distinct Hsp90 dimer conformations (17-19). Interestingly, apo Hsp90 forms a wide-open, V-shaped dimer with the N domains separated by as much as 101 Å (18). This open conformation is markedly distinct from the intertwined, N-terminally closed dimer with ATP bound (20,21). Because the open-state dimer cannot signal the nucleotide status between neighboring subunits, an intermediate conformation preceding dimer closure must exist, which so far has remained elusive.Apart from cytosolic Hsp90s, Hsp90 homologs are found in the endoplasmic reticulum, chloroplasts, and mitochondria ( Fig. S1) (22). The tumor necrosis factor receptor-associated protein 1 (TRAP1) is the mitochondrial Hsp90 paralog, which prevents apoptosis and protects mitochondria against oxidative damage (23-25). TRAP1 is widely expressed in many tumors (24,26,27), but not in mitochondria of most normal tissues (24), benign prostatic hyperplasia (26), or highly proliferating, nontransformed cells (27). Notably, it was found that TRAP1 not only promotes neoplastic growth, but also confers tumorigenic potential on nontransformed cells (27), indicating a major rol...

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Section: Discussionmentioning

confidence: 81%

Mitochondrial Hsp90 is a ligand-activated molecular chaperone coupling ATP binding to dimer closure through a coiled-coil intermediate

Sung

Lee

Kim

et al. 2016

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

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“…This observation led to the proposal that Hsp90C participates with other stromal chaperones as part of the import motor. This hypothesis is supported by studies in cyanobacteria, Chlamydomonas and Arabidopsis demonstrating that the bacterial/organelle Hsp70 and Hsp90 family members interact in complexes containing additional co-chaperones [171-173]. …”

Section: Nature and Function Of Tic Complexesmentioning

confidence: 93%

New Insights into the Mechanism of Chloroplast Protein Import and Its Integration with Protein Quality Control, Organelle Biogenesis and Development

Paila

Richardson

Schnell

2015

Journal of Molecular Biology

137

140

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The translocons at the outer (TOC) and inner (TIC) envelope membranes of chloroplasts mediate the targeting and import of several thousand nuclear encoded preproteins that are required for organelle biogenesis and homeostasis. The cytosolic events in preprotein targeting remain largely unknown, although cytoplasmic chaperones have been proposed to facilitate delivery to the TOC complex. Preprotein recognition is mediated by the TOC GTPase receptors, Toc159 and Toc34. The receptors constitute a GTP-regulated switch, which initiates membrane translocation via Toc75, a member of the OMP85 (Outer Membrane Protein 85)/TpsB (two partner secretion system B) family of bacterial, plastid and mitochondrial β-barrel outer membrane proteins. The TOC receptor systems have diversified to recognize distinct sets of preproteins, thereby maximizing the efficiency of targeting in response to changes in gene expression during developmental and physiological events that impact organelle function. The TOC complex interacts with the TIC translocon to allow simultaneous translocation of preproteins across the envelope. Two inner membrane complexes, the Tic110 and 1 MDa complexes, have both been implicated as constituents of the TIC translocon, and it remains to be determined how they interact to form the TIC channel and assemble the import-associated chaperone network in the stroma that drives import across the envelope membranes. This review will focus on recent developments in our understanding of the mechanisms and diversity of the TOC-TIC systems. Our goal is to incorporate these recent studies with previous work and present updated or revised models for the function of TOC-TIC in protein import.

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“…Hitoshi Nakamoto (Saitama University, Saitama, Japan) showed that a cyanobacterial mutant of HtpG is impaired under heat stress. HtpG and DnaK were found to directly interact (whereas in eukaryotes this is mediated by HOP), and HtpG to collaborate with DnaK to assist in refolding of denatured proteins in either an ATP-dependent or an ATPindependent fashion 15 . Contrary to expectations, DnaK-HtpG collaboration in an m e e t i n g r e p o r t npg the mechanisms by which Hsp90 recognizes non-native states of client proteins can be explored.…”

Section: Hsp90 Orthologs: Grp94 and Htpgmentioning

confidence: 99%

The Hsp90 ensemble: coordinated Hsp90–cochaperone complexes regulate diverse cellular processes

Schwenkert

Hugel

Cox

2014

Nat Struct Mol Biol

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Physical Interaction between Bacterial Heat Shock Protein (Hsp) 90 and Hsp70 Chaperones Mediates Their Cooperative Action to Refold Denatured Proteins

Cited by 65 publications

References 37 publications

Mitochondrial Hsp90 is a ligand-activated molecular chaperone coupling ATP binding to dimer closure through a coiled-coil intermediate

Mitochondrial Hsp90 is a ligand-activated molecular chaperone coupling ATP binding to dimer closure through a coiled-coil intermediate

New Insights into the Mechanism of Chloroplast Protein Import and Its Integration with Protein Quality Control, Organelle Biogenesis and Development

The Hsp90 ensemble: coordinated Hsp90–cochaperone complexes regulate diverse cellular processes

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