The mode of action of peptidyl prolyl <i>cis/trans</i> isomerases in vivo: binding vs. catalysis

Fischer, Gunter; Tradler, Thomas; Zarnt, Toralf

doi:10.1016/s0014-5793(98)00242-7

Cited by 114 publications

(91 citation statements)

References 44 publications

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“…CsA is a well known immunosuppressive drug that binds to cyclophilins, a family of ubiquitous and conserved proteins with peptidyl-prolyl cis-trans isomerase and molecular chaperone activities (23,24). We now show, for the first time, that CsA specifically stimulates Pro-564 hydroxylation.…”

Section: Discussionmentioning

confidence: 99%

Cyclosporin A Prevents the Hypoxic Adaptation by Activating Hypoxia-inducible Factor-1α Pro-564 Hydroxylation

D’Angelo¹,

Duplan²,

Vigne

et al. 2003

Journal of Biological Chemistry

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Cells respond to low oxygen tensions by up-regulating the expression of genes involved in angiogenesis (e.g. vascular endothelial growth factor), erythropoiesis (e.g. erythropoietin), and glycolysis. The transcriptional activation of target genes is induced by a common transcription factor, hypoxia-inducible factor-1 (HIF-1). 1 HIF-1 was first identified as a heterodimeric transactivator that recognizes a specific DNA sequence, termed hypoxia-responsive element (HRE) in the 3Ј-untranslated region of the erythropoietin gene (1). HIF-1 consists of two subunits, HIF-1␣ and the aryl hydrocarbon receptor nuclear translocator, both of which belong to the large family of basic helixloop-helix-per-arnt-sim transcription factors (2, 3). Under normoxic conditions, HIF-1␣ subunits are unstable, being rapidly targeted to the ubiquitin-proteasome pathway. Degradation is mediated by a ubiquitin-protein isopeptide ligase (E3) complex, in which the von Hippel-Lindau protein (vHL) binds to a specific hydroxylated proline residue (Pro-564) within the oxygen-dependent degradation (ODD) domain of HIF-1␣ (4, 5). A major action of hypoxia is to suppress prolyl hydroxylation and degradation of HIF-1␣ by the proteasome. As a consequence, the protein accumulates, migrates to the nucleus, and associates with the aryl hydrocarbon receptor nuclear translocator, and the complex interacts with the HRE of target genes (6, 7). The importance of this mechanism is ascertained by the facts that vessel formation is hampered in HIF-1␣ Ϫ/Ϫ knock out mice (8) and that mutations in the vHL gene cause hereditary cancer syndrome associated with dysregulated angiogenesis and up-regulation of hypoxia-sensitive genes.Cyclosporin A (CsA) is a potent immunosuppressive agent used after organ transplantation and in the treatment of several autoimmune diseases. CsA is well known to be nephrotoxic probably as a consequence of the constriction of renal vessels and of the resulting hypoxia. Circumstantial evidence further suggests that CsA interferes with the hypoxic signaling cascade. (i) Maruyama et al. (9) reported that CsA inhibited vascular endothelial growth factor production by human lymphocytes. (ii) CsA inhibits erythropoietin production in anemic mice (10). (iii) Kang et al. (11) reported that vascular endothelial growth factor reverses some of the post-CsA-mediated hypertension and nephropathy in the rat. (iv) Erythropoietin deficiency has been proposed as a cause of the anemia observed in children following cardiac transplantation (12). These would suggest that CsA inhibits the cellular responses that are mediated by HIF-1␣ and HRE.In the present study, we examine the possible influence of CsA on the hypoxic signaling. Results show that CsA inhibits hypoxia-induced gene transcription by preventing hypoxia-induced and ODD-dependent stabilization of HIF-1␣. We also show that CsA stimulates a kidney prolyl hydroxylase activity that specifically modifies Pro-564 in the ODD domain of HIF-1␣. MATERIALS AND METHODSMaterials-Culture medium, restriction, and ...

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Section: Discussionmentioning

confidence: 99%

Cyclosporin A Prevents the Hypoxic Adaptation by Activating Hypoxia-inducible Factor-1α Pro-564 Hydroxylation

D’Angelo¹,

Duplan²,

Vigne

et al. 2003

Journal of Biological Chemistry

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“…PPIases catalyze isomerization around peptidyl-prolyl imide bonds in peptides and proteins serving as protein folding catalysts [7,8] as well as regulators of diverse cellular processes including cell signaling, biogenesis and activities of several receptors (reviewed in [9,10]). These enzymes belong to three families: cyclophilins, FK506 binding proteins (FKBPs) and parvulins [9].…”

Section: Introductionmentioning

confidence: 99%

The major peptidyl‐prolyl isomerase activity in thylakoid lumen of plant chloroplasts belongs to a novel cyclophilin TLP20

Edvardsson¹,

Eshaghi²,

Vener³

et al. 2003

FEBS Letters

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Fractionation of proteins from the thylakoid lumen of spinach chloroplasts combined with peptidyl-prolyl cis/trans isomerase (PPIase) measurements revealed a major isomerase activity that was ascribed to a novel enzyme TLP20 (thylakoid lumen PPIase of 20 kDa). TLP20 was inhibited by cyclosporin A and mass spectrometric sequencing of tryptic peptides con¢rmed its classi¢cation as a cyclophilin. Genes encoding similar putative thylakoid cyclophilins with a unique insert of three amino acids NPV in their N-termini were found in chromosome 5 of both Arabidopsis and rice. TLP20 is suggested to be the major PPIase and protein folding catalyst in the thylakoid lumen of plant chloroplasts. ß

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“…Interestingly, only a few proteins are known to exhibit such conformational heterogeneity for a prolyl peptide bond in the folded state (ref. 26 and references therein) and, thus far, catalysis of those prolyl peptide bonds by PPIases could not be detected when assayed (27). An intriguing hypothesis for the role of CypA in HIV-1 virulence is that it catalyzes cis͞trans isomerization about G89-P90 in CA N , resulting in a conformational change necessary for CA core disassembly (23).…”

mentioning

confidence: 99%

Catalysis of cis/trans isomerization in native HIV-1 capsid by human cyclophilin A

Bosco

Eisenmesser

Pochapsky

et al. 2002

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

208

211

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Packaging of cyclophilin A (CypA) into HIV-1 virions is essential for efficient replication; however, the reason for this is unknown. Incorporation is mediated through binding to the Gly-89 -Pro-90 peptide bond of the N-terminal domain of HIV-1 capsid (CA N ). Despite the fact that CypA is a peptidyl-prolyl cis͞trans isomerase, catalytic activity on CA N has not been observed previously. We show here, using NMR exchange spectroscopy, that CypA does not only bind to CA N but also catalyzes efficiently the cis͞trans isomerization of the Gly-89 -Pro-90 peptide bond. In addition, conformational changes in CA N distal to the CypA binding loop are observed on CypA binding and catalysis. The results provide experimental evidence for efficient CypA catalysis on a natively folded and biologically relevant protein substrate.

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The mode of action of peptidyl prolyl cis/trans isomerases in vivo: binding vs. catalysis

Cited by 114 publications

References 44 publications

Cyclosporin A Prevents the Hypoxic Adaptation by Activating Hypoxia-inducible Factor-1α Pro-564 Hydroxylation

Cyclosporin A Prevents the Hypoxic Adaptation by Activating Hypoxia-inducible Factor-1α Pro-564 Hydroxylation

The major peptidyl‐prolyl isomerase activity in thylakoid lumen of plant chloroplasts belongs to a novel cyclophilin TLP20

Catalysis of cis/trans isomerization in native HIV-1 capsid by human cyclophilin A

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