d-Peptides as Inhibitors of the DnaK/DnaJ/GrpE Chaperone System

Bischofberger, Pius; Han, Wanjiang; Feifel, Bastian; Schönfeld, Hans‐Joachim; Christen, Philipp

doi:10.1074/jbc.m300922200

Cited by 38 publications

(25 citation statements)

References 17 publications

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“…Luciferase activity was measured as described previously (43,55,56). In the presence of oxygen, luciferase catalyzes the conversion of D-luciferin and ATP into oxiluciferin, CO 2 , AMP, PPi, and photons.…”

Section: Methodsmentioning

confidence: 99%

Cadmium Causes Misfolding and Aggregation of Cytosolic Proteins in Yeast

Jacobson

Priya

Sharma

et al. 2017

Molecular and Cellular Biology

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Cadmium is a highly poisonous metal and is classified as a human carcinogen. While its toxicity is undisputed, the underlying in vivo molecular mechanisms are not fully understood. Here, we demonstrate that cadmium induces aggregation of cytosolic proteins in living Saccharomyces cerevisiae cells. Cadmium primarily targets proteins in the process of synthesis or folding, probably by interacting with exposed thiol groups in not-yet-folded proteins. On the basis of in vitro and in vivo data, we show that cadmium-aggregated proteins form seeds that increase the misfolding of other proteins. Cells that cannot efficiently protect the proteome from cadmium-induced aggregation or clear the cytosol of protein aggregates are sensitized to cadmium. Thus, protein aggregation may contribute to cadmium toxicity. This is the first report on how cadmium causes misfolding and aggregation of cytosolic proteins in vivo. The proposed mechanism might explain not only the molecular basis of the toxic effects of cadmium but also the suggested role of this poisonous metal in the pathogenesis of certain protein-folding disorders.

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Section: Methodsmentioning

confidence: 99%

Cadmium Causes Misfolding and Aggregation of Cytosolic Proteins in Yeast

Jacobson

Priya

Sharma

et al. 2017

Molecular and Cellular Biology

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“…The intermolecular interaction is slow because the formation of the complex of the two molecules involves a considerable loss of entropy, whereas the intracomplex interaction results in little loss of entropy (29,30). The cis-interaction of DnaJ with DnaK seems to be essential for efficient chaperone action in the refolding of denatured luciferase (31). Because the interaction of DnaJ and DnaK is transient (5,6,32), DnaJ may trigger spatially close DnaK molecules in succession, converting them from their ATP-liganded state to the ADP-liganded state.…”

Section: In the Presence Of A Protein Substrate The Co-chaperone Actmentioning

confidence: 99%

Mechanism of the Targeting Action of DnaJ in the DnaK Molecular Chaperone System

Han

Christen

2003

Journal of Biological Chemistry

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112

104

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In the DnaK (Hsp70) molecular chaperone system of Escherichia coli, the substrate polypeptide is fed into the chaperone cycle by association with the fast-binding, ATP-liganded form of the DnaK. The substrate binding properties of DnaK are controlled by its two cochaperones DnaJ (Hsp40) and GrpE. DnaJ stimulates the hydrolysis of DnaK-bound ATP, and GrpE accelerates ADP/ATP exchange. DnaJ has been described as targeting the substrate to DnaK, a concept that has remained rather obscure. Based on binding experiments with peptides and polypeptides we propose here a novel mechanism for the targeting action of DnaJ: ATP⅐DnaK and DnaJ with its substrate-binding domain bind to different segments of one and the same polypeptide chain forming (ATP⅐DnaK) m ⅐substrate⅐DnaJ n complexes; in these ternary complexes efficient cis-interaction of the J-domain of DnaJ with DnaK is favored by their propinquity and triggers the hydrolysis of DnaK-bound ATP, converting DnaK to its ADP-liganded high affinity state and thus locking it onto the substrate polypeptide. Hsp70 1 chaperones assist a variety of protein folding processes in the cell, including folding of nascent polypeptide chains, rescue of misfolded proteins, translocation of polypeptide chains through membranes, assembly and disassembly of protein complexes, and control of the biological activity of folded regulatory proteins (for a review, see Ref. 1). The chaperone action of DnaK, an Hsp70 homolog in Escherichia coli, is driven by the hydrolysis of ATP. DnaJ, an Hsp40 homolog, triggers the hydrolysis of DnaK-bound ATP and thus converts DnaK from the ATP-liganded low affinity T state to its ADPliganded high affinity R state (2-6). The stimulation of the ATPase activity requires the conserved J-domain of DnaJ (residues 2-78 in E. coli DnaJ; Refs. 2, 4, and 7) and the adjacent G/F region (2). DnaJ itself is also capable of associating with unfolded substrates and preventing aggregation (8 -11), qualifying DnaJ as a chaperone on its own. Binding of substrates requires the zinc finger-like region and the COOH-terminal region of DnaJ (12). Only full-length DnaJ, comprising both the J-domain and the substrate-binding domain, is effective, together with DnaK and GrpE, in refolding denatured firefly luciferase (12, 13). Based on these findings, it has been proposed that substrates first associate with DnaJ, which then transfers them to the substrate-binding site of Hsp70 (6,10,11,14). The function of DnaJ has also been assumed to include a "catalytic activation" of DnaK for trapping target sequences (4, 15). A recent study has shown that DnaJ shares most binding motifs with DnaK, which also seems to qualify DnaJ as a targeting partner for the chaperone DnaK (16).However, no direct experimental evidence has been reported for substrate transfer from DnaJ to DnaK, and the concept of a targeting action of DnaJ has as yet remained obscure (16). The catalytic activation of DnaK by DnaJ (4, 15) has not remained undisputed (17). Recent work (6) has shown that the stimulatory effect of Dn...

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“…D-peptides have been shown to interact with chaperone systems. For example, D-peptides compete with L-peptides for the same binding site in DnaJ, and this interaction can inhibit refolding functions of this chaperone system (Bischofberger et al, 2003). In addition, all D-and all L-conformers of the functional element of ␣A-crystallin do not show marked differences in their chaperone-like activity (Bhattacharyya and Sharma, 2001).…”

Section: Downloaded Frommentioning

confidence: 99%

Protective Peptides That Are Orally Active and Mechanistically Nonchiral

Brenneman

Spong

Hauser

et al. 2004

J Pharmacol Exp Ther

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Previous reports identified two peptides that mimic the action of neuroprotective proteins derived from astrocytes. These peptides, NAPVSIPQ and SALLRSIPA, prevent neuronal cell death produced by electrical blockade, N-methyl-D-aspartate, and ␤-amyloid peptide (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). In the present study, all Damino acid peptides of NAPVSIPQ and SALLRSIPA were synthesized and compared respectively to the corresponding all L-amino acid peptides. In rat cerebral cortical test cultures cotreated with 1 M tetrodotoxin, the D-amino acid peptides produced similar potency and efficacy for neuroprotection as that observed for their respective L-amino acid peptides. Since all these peptides tested individually exhibited attenuation of efficacy at concentrations of Ͼ10 pM, combinations of these peptides were tested for possible synergies. Equimolar D-NAPVSIPQ and D-SALLRSIPA combination treatment produced potent neuroprotection (EC 50 , 0.03 fM) that did not attenuate with increasing concentrations. Similarly, the combination of L-NAPVSIPQ and D-SALLRSIPA also had high potency (EC 50 , 0.07 fM) without attenuation of efficacy. Combined administration of peptides was tested in a model of fetal alcohol syndrome and in a model of learning impairment: apolipoprotein E knockout mice. Intraperitoneal administration of D-NAPV-SIPQ plus D-SALLRSIPA to pregnant mice (embryonic day 8) attenuated fetal demise after treatment with an acute high dose of alcohol. Furthermore, oral administration of D-NAPVSIPQ plus D-SALLRSIPA significantly increased fetal survival after maternal alcohol treatment. Apolipoprotein E knockout mice injected with D-NAPVSIPQ plus D-SALLRSIPA showed improved performance in the Morris water maze. These studies suggest therapeutic potential for the combined administration of neuroprotective peptides that can act through a mechanism independent of chiral recognition.

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d-Peptides as Inhibitors of the DnaK/DnaJ/GrpE Chaperone System

Cited by 38 publications

References 17 publications

Cadmium Causes Misfolding and Aggregation of Cytosolic Proteins in Yeast

Cadmium Causes Misfolding and Aggregation of Cytosolic Proteins in Yeast

Mechanism of the Targeting Action of DnaJ in the DnaK Molecular Chaperone System

Protective Peptides That Are Orally Active and Mechanistically Nonchiral

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