F1F0-ATP synthase functions as a co-chaperone of Hsp90–substrate protein complexes

Papathanassiu, Adonia E.; MacDonald, Nicholas J.; Bencsura, Ákos; Vu, Hong

doi:10.1016/j.bbrc.2006.04.104

Cited by 33 publications

(37 citation statements)

References 26 publications

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“…Rotenone inhibits OXPHOS at complex I, TFFA at complex II, and antimycin at complex III (Ramsay et al 1981;Teeter et al 1969). Oligomycin is another inhibitor of F 1 F 0 -ATPase, which also suppresses Hsp90 chaperone function through dissociation of the Hsp90:F 1 F 0 -ATPase complex (Papathanassiu et al 2006). Unlike EF, oligomycin is not a proteasome inhibitor.…”

Section: Atp Depletionmentioning

confidence: 99%

“…In MCF-7 cells, inhibition of F 1 F 0 -ATPase by EF leads to dissociation of the Hsp90:F 1 F 0 -ATPase complex and inhibition of the Hsp90 chaperone activity (Papathanassiu et al 2006). To examine if the mechanism is also functional in the MDA-MB-231 cells, the cells were exposed briefly (10 min) to various concentrations of EF.…”

Section: Inhibition Of Hsp90 and Proteasomementioning

confidence: 99%

“…We have previously shown that inhibition of Hsp90 function by EF is independent of the intracellular concentration of ATP (Papathanassiu et al 2006). To evaluate if inhibition of cell proliferation by EF is also ATPindependent, the levels of ATP following exposure of the MCF-7, T47D, MDA-MB-453, and MDA-MB-231 cells to EF for 24 h were assessed (Fig.…”

Section: Atp Depletionmentioning

confidence: 99%

“…These experiments were performed essentially as previously described (Papathanassiu et al 2006). Experiments were performed at least twice.…”

Section: Co-immunoprecipitation and Western Immunoblotting Experimentsmentioning

confidence: 99%

“…One set of plates was used to determine intracellular ATP concentrations as previously described (Papathanassiu et al 2006) with the notable exception that cells were treated with ATPase inhibitors for 24 h. The other set of plates was used to estimate cell numbers by Cyquant. At the end of the experiment, ATP levels were normalized per cell number and expressed as percent of normalized ATP values found in control (untreated) cells.…”

Section: Atpase Assaymentioning

confidence: 99%

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Antitumor activity of efrapeptins, alone or in combination with 2-deoxyglucose, in breast cancer in vitro and in vivo

Papathanassiu

MacDonald

Emlet

et al. 2011

Cell Stress and Chaperones

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Efrapeptins (EF), a family of fungal peptides, inhibit proteasomal enzymatic activities and the in vitro and in vivo growth of HT-29 cells. They are also known inhibitors of F 1 F 0 -ATPase, a mitochondrial enzyme that functions as an Hsp90 co-chaperone. We have previously shown that treatment of cancer cells with EF results in disruption of the Hsp90:F 1 F 0 -ATPase complex and inhibition of Hsp90 chaperone activity. The present study examines the effect of EF on breast cancer growth in vitro and in vivo. As a monotherapy, EF inhibited cell proliferation in vitro with an IC 50 value ranging from 6 nM to 3.4 μM. Inhibition of Hsp90 chaperone function appeared to be the dominant mechanism of action and the factor determining cellular sensitivity to EF. In vitro inhibition of proteasome became prominent in the absence of adequate levels of Hsp90 and F 1 F 0 -ATPase as in the case of the relatively EF-resistant MDA-MB-231 cell line. In vivo, EF inhibited MCF-7 and MDA-MB-231 xenograft growth with a maximal inhibition of 60% after administration of 0.15 and 0.3 mg/kg EF, respectively. 2-Deoxyglucose (2DG), a known inhibitor of glycolysis, acted synergistically with EF in vitro and antagonistically in vivo. In vitro, the synergistic effect was attributed to a prolonged endoplasmic reticulum (ER) stress. In vivo, the antagonistic effect was ascribed to the downregulation of tumoral and/or stromal F 1 F 0 -ATPase by 2DG.

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Section: Atp Depletionmentioning

confidence: 99%

Section: Inhibition Of Hsp90 and Proteasomementioning

confidence: 99%

Section: Atp Depletionmentioning

confidence: 99%

“…These experiments were performed essentially as previously described (Papathanassiu et al 2006). Experiments were performed at least twice.…”

Section: Co-immunoprecipitation and Western Immunoblotting Experimentsmentioning

confidence: 99%

Section: Atpase Assaymentioning

confidence: 99%

See 3 more Smart Citations

Antitumor activity of efrapeptins, alone or in combination with 2-deoxyglucose, in breast cancer in vitro and in vivo

Papathanassiu

MacDonald

Emlet

et al. 2011

Cell Stress and Chaperones

Self Cite

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Conformational Properties of Secondary Amino Acids: Replacement of Pipecolic Acid by N‐Methyl‐L‐alanine in Efrapeptin C

Konar

Vass

Hollósi

et al. 2013

Chemistry & Biodiversity

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The efrapeptins, a family of naturally occurring peptides with inhibitory activities against ATPases, contain several α,α-disubstituted α-amino acids such as α-aminoisobutyric acid (Aib) or isovaline (Iva) besides pipecolic acid (Pip), β-Ala, Leu, Gly, and a C-terminal heterocyclic residue. Secondary α-amino acids such as proline are known to stabilize discrete conformations in peptides. A similar influence is ascribed to N-alkyl α-amino acids. We synthesized two efrapeptin C analogs with replacement of Pip by N-methyl-L-alanine (MeAla) using a combination of solid- and solution-phase techniques in a fragment-condensation strategy to compare the conformational bias of both secondary amino acids. The solution conformation was investigated by vibrational circular dichroism (VCD) to probe whether the analogs adopt a 310 -helical conformation. The MeAla-containing analogs [MeAla(1,3) ]efrapeptin C and [MeAla(1,3,11) ]efrapeptin C inhibit ATP hydrolysis by the A3 B3 complex of A1 A0 -ATP synthase from Methanosarcina mazei Gö1.

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Sequences of Tolypins, Insecticidal Efrapeptin‐Type Peptaibiotics from Species of the Fungal Genus Tolypocladium

Brückner

Degenkolb

2020

Chemistry & Biodiversity

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A peptide mixture named tolypin, originally isolated from species of the fungal genus Tolypocladium, was structurally characterised and sequences compared to those reported for efrapeptins isolated from strains of Tolypocladium inflatum. Chiral amino acid analysis, direct infusion, and online HPLC electrospray ionization tandem mass spectrometry provided composition, molecular weights of peptides, and series of diagnostic fragment ions. Sequences deduced from ESI‐MS revealed that tolypins C−G are identical to efrapeptins C−G. The results were corroborated by ESI‐MS and HPLC of an authentic efrapeptin sample from Eli Lilly Research Laboratories (USA). Comparison of the HPLC elution profiles of efrapeptin and tolypin indicated a pronounced microheterogeneity of the former. A high‐resolution HPLC of authentic efrapeptin has not been published before. Close relationship and partial identity of sequences of tolypins and efrapeptins, which had previously been postulated, were definitely proven. The geographical origin of the two most important T. inflatum strains used for sequencing of efrapeptins/tolypins could unambiguously be clarified. A new minor compound, designated tolypin H1, was sequenced. High proportions of helicogenic Aib (α‐aminoisobutyric acid) and l‐isovaline, N‐terminal acetyl‐l‐pipecolic acid and the unusual, amide‐bound C‐terminal residue, named (S)‐2‐amino‐1‐(1,5‐diazabicyclo[4.3.0]non‐5‐ene‐5‐ylium)‐4‐methylpentane corresponding to 1‐[(2S)‐2‐amino‐4‐methylpentyl]‐2,3,4,6,7,8‐hexahydropyrrolo[1,2‐a]pyrimidin‐1‐ium, define these peptides as linear, cationic peptaibiotics.

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F1F0-ATP synthase functions as a co-chaperone of Hsp90–substrate protein complexes

Cited by 33 publications

References 26 publications

Antitumor activity of efrapeptins, alone or in combination with 2-deoxyglucose, in breast cancer in vitro and in vivo

Antitumor activity of efrapeptins, alone or in combination with 2-deoxyglucose, in breast cancer in vitro and in vivo

Conformational Properties of Secondary Amino Acids: Replacement of Pipecolic Acid by N‐Methyl‐L‐alanine in Efrapeptin C

Sequences of Tolypins, Insecticidal Efrapeptin‐Type Peptaibiotics from Species of the Fungal Genus Tolypocladium

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