Peptidylproline cis/trans isomerases

Gałat, Andrzej; Metcalfe, Su

doi:10.1016/0079-6107(94)00009-x

Cited by 221 publications

(173 citation statements)

References 333 publications

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“…As reported by Hottenrott et al (1997), SlyD acts as an isomerase. FK506-binding proteins (FKBPs) form a large family of proteins possessing a minimum 100 amino acid domain with peptidyl-prolyl cis-trans isomerase activity (Galat and Metcalfe, 1995). This activity can be inhibited by the immunosuppressive drug, FK506, which occupies the catalytic site.…”

Section: Figmentioning

confidence: 99%

Proline 21, a residue within the α‐helical domain of ΦX174 lysis protein E, is required for its function in Escherichia coli

Witte

Schrot

Schön

et al. 1997

Molecular Microbiology

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Summary⌽X174 lysis protein E-mediated lysis of Escherichia coli is characterized by a protein E-specific fusion of the inner and outer membrane and formation of a transmembrane tunnel structure. In order to understand the fusion process, the topology of protein E within the envelope complex of E. coli was investigated. Proteinase K protection studies showed that, during the time course of protein E-mediated lysis process, more of the fusion protein E-FXa-streptavidin gradually became accessible to the protease at the cell surface. These observations postulate a conformational change in protein E during induction of the lysis process by movement of the C-terminal end of the protein throughout the envelope complex from the inner side to the outer side spanning the entire pore and fusing the inner and outer membranes at distinct areas. The initiation mechanism for such a conformational change could be the cis-trans isomerization of proline residues within ␣-helical membrane-spanning segments. Conversion of proline 21, presumed to be in the membrane-embedded ␣-helix of protein E, to alanine, glycine, serine and valine, respectively, resulted in lysis-negative E mutant proteins. Proteinase K accessibility studies using streptavidin as a reporter fused to the P21G mutant protein showed that the C-terminal part of the fusion protein is not translocated to the outer side of the membrane, suggesting that this proline residue is essential for the correct folding of protein E within the cell wall complex of E. coli. Oligomerization of protein P21G-StrpA was not disturbed.

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Section: Figmentioning

confidence: 99%

Proline 21, a residue within the α‐helical domain of ΦX174 lysis protein E, is required for its function in Escherichia coli

Witte

Schrot

Schön

et al. 1997

Molecular Microbiology

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“…The isomerization of these bonds is a slow process (2) and often a rate-determining step in protein folding (3)(4)(5)(6). PPIases have been found in all organisms and subcellular compartments studied so far (1,7,8). Until now three unrelated families of PPIases could be identified: parvulins, cyclophilins, and FKBPs (1,5,9).…”

Section: Ppiasesmentioning

confidence: 99%

Cpr6 and Cpr7, Two Closely Related Hsp90-associated Immunophilins from Saccharomyces cerevisiae, Differ in Their Functional Properties

Mayr

Richter

Lilie

et al. 2000

Journal of Biological Chemistry

105

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Hsp90 is an abundant cytosolic molecular chaperone. It controls the folding of target proteins including steroid hormone receptors and kinases in complex with several partner proteins. Prominent members of this protein family are large peptidyl prolyl cis/trans isomerases (PPIases), which catalyze the cis/trans isomerization of prolyl peptide bonds in proteins and possess chaperone activity. In Saccharomyces cerevisiae, two closely related large Hsp90-associated PPIases, Cpr6 and Cpr7, exist. We show here that these homologous proteins bind with comparable affinity to Hsp90 but exhibit significant structural and functional differences. Cpr6 is more stable than Cpr7 against thermal denaturation and displays an up to 100-fold higher PPIase activity. In contrast, the chaperone activity of Cpr6 is much lower than that of Cpr7. Based on these results we suggest that the two immunophilins perform overlapping but not identical tasks in the Hsp90 chaperone cycle. PPIases1 are enzymes that are able to catalyze the cis-trans isomerization of Xaa-Pro peptide bonds in short synthetic peptides as well as in proteins (1). The isomerization of these bonds is a slow process (2) and often a rate-determining step in protein folding (3-6). PPIases have been found in all organisms and subcellular compartments studied so far (1,7,8). Until now three unrelated families of PPIases could be identified: parvulins, cyclophilins, and FKBPs (1,5,9). Because of their inhibition by the immunosuppressive drugs cyclosporin A (CsA) or FK506/rapamycin, the cyclophilins and FKBPs are also termed immunophilins (10 -13). Several large immunophilins with a molecular mass of about 40 -54 kDa are components of the Hsp90 chaperone complex. In higher eukaryotes, FKBP51, FKBP52, and Cyp40 act together with Hsp90; in yeast these are Cpr6 and Cpr7, two cyclophilins. The Hsp90 complex seems to regulate the conformation of its target proteins. These substrates include steroid hormone receptors. Here, the Hsp90 chaperone cycle is well established (reviewed in Refs. 14 -16).In the case of the progesterone receptor, the receptor is bound to Hsp70 in an early complex (15,17). Then an intermediate complex is formed in which Hsp90, Hsp70, Hip, Hop, and perhaps Hsp40 participate. The last step of this activation cycle is a complex, consisting of the progesterone receptor, Hsp90, p23, and one of the large immunophilins. The specific function of the immunophilins in the chaperone cycle is far from clear. However, it is well established that progesterone receptor has to be bound in this complex to allow binding of the hormone, dimerization, and subsequently, interaction with DNA. In the absence of hormone, the receptor is released from the complex, and the cycle starts again. The large immunophilins interact with Hsp90 via tetratricopeptide repeats (18 -21). The partner site for the tetratricopeptide-repeat motifs is located in a 12-kDa carboxyl-terminal domain of Hsp90 (22, 23). The tetratricopeptide-repeat proteins compete with each other for this binding site (18,1...

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“…Cyclophilins play a role in protein folding mediated by their PPI domain, which catalyzes the isomerization of X-proline peptide bonds, 34 and via their chaperone activity. [35][36][37] Binding of CsA to CyPA leads to inhibition of the Ca 2ϩ -and calmodulin-dependent phosphatase calcineurin and inhibits the PPIase and chaperone activity of CyPA.…”

Section: Enzymatic Activity Of Cypa Is Responsible For Defective Ca 2mentioning

confidence: 99%

Intracellular cyclophilin A is an important Ca2+ regulator in platelets and critically involved in arterial thrombus formation

Elvers

Herrmann

Seizer

et al. 2012

Blood

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Platelet adhesion and aggregation play a critical role in primary hemostasis. Uncontrolled platelet activation leads to pathologic thrombus formation and organ failure. The decisive central step for different processes of platelet activation is the increase in cytosolic Ca 2؉ activity ([Ca 2؉ ] i ). Activation-dependent depletion of intracellular Ca 2؉ stores triggers Ca 2؉ entry from the extracellular space. Stromal interaction molecule 1 (STIM1) has been identified as a Ca 2؉ sensor that regulates store-operated Ca 2؉ entry through activation of the pore-forming subunit Orai1, the major store-operated Ca 2؉ entry channel in platelets. In the present study, we show for the first time that the chaperone protein cyclophilin A (CyPA) acts as a Ca 2؉ modulator in platelets. CyPA deficiency strongly blunted activation-induced Ca 2؉ mobilization from intracellular stores and Ca 2؉ influx from the extracellular compartment and thus impaired platelet activation substantially. Furthermore, the phosphorylation of the Ca 2؉ sensor STIM1 was abrogated upon CyPA deficiency, as shown by immunoprecipitation studies. In a mouse model of arterial thrombosis, CyPAdeficient mice were protected against arterial thrombosis, whereas bleeding time was not affected. The results of the present study identified CyPA as an important Ca 2؉ regulator in platelets, a critical mechanism for arterial thrombosis. IntroductionPlatelet adhesion and aggregation are essential for hemostasis at sites of vascular injury to avoid excessive blood loss. 1,2 In contrast, uncontrolled platelet activation can induce acute vessel occlusion, leading to myocardial infarction or stroke at areas of atherosclerotic plaque rupture. 3,4 Platelet activation and thrombus formation is a multistage process that involves different signaling pathways to trigger platelet shape change, integrin activation, and degranulation. 4,5 The signaling pathways converge in the activation of phospholipase C (PLC), leading to the formation of inositol 1,4,5-triphosphate (IP 3 ) and diacylglycerol. 6 IP 3 is then able to bind to its receptor at the endoplasmic reticulum (ER) and mediates Ca 2ϩ efflux from the intracellular stores into the cytoplasm. 6,7 Compromised PLC activation impairs Ca 2ϩ mobilization, which is followed by defective thrombus formation under flow conditions. 8,9 Stromal interaction molecule 1 (STIM1) is a type I singletransmembrane protein with an N-terminal EF hand domain (helix-loop-helix structural domain) that binds Ca 2ϩ in the lumen of the ER. STIM1 binding to Ca 2ϩ is interrupted upon store release and induces redistribution of STIM1 to the plasma membrane to open store-operated Ca 2ϩ (SOC) channels, thereby stimulating store-operated Ca 2ϩ entry (SOCE). 10,11 Orai1 was identified as the major SOCE channel in platelets known to be regulated by the Ca 2ϩ sensor STIM1. 12,13 Immunophilins are endogenous cytosolic peptidyl-prolyl isomerases (PPIs) that interconvert between the cis and trans positions of target proteins. 14,15 According to their sensitivity t...

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Peptidylproline cis/trans isomerases

Cited by 221 publications

References 333 publications

Proline 21, a residue within the α‐helical domain of ΦX174 lysis protein E, is required for its function in Escherichia coli

Proline 21, a residue within the α‐helical domain of ΦX174 lysis protein E, is required for its function in Escherichia coli

Cpr6 and Cpr7, Two Closely Related Hsp90-associated Immunophilins from Saccharomyces cerevisiae, Differ in Their Functional Properties

Intracellular cyclophilin A is an important Ca2+ regulator in platelets and critically involved in arterial thrombus formation

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