A single Trp121 to Ala121 mutation in human cyclophilin alters cyclosporin A affinity and peptidyl-prolyl isomerase activity

1991 ◽  
Vol 176 (3) ◽  
pp. 1142-1148 ◽  
Author(s):  
Mary J. Bossard ◽  
Paul L. Koser ◽  
Martin Brandt ◽  
Derk J. Bergsma ◽  
Mark A. Levy
Keyword(s):  
Cyclosporin A ◽  
Prolyl Isomerase ◽  
Peptidyl Prolyl Isomerase ◽  
Isomerase Activity

scholarly journals Active site mutants of human cyclophilin A separate peptidyl-prolyl isomerase activity from cyclosporin A binding and calcineurin inhibition

1992 ◽  
Vol 1 (9) ◽  
pp. 1092-1099 ◽  
Author(s):  
Lynne D. Zydowsky ◽  
Felicia A. Etzkorn ◽  
Howard Y. Chang ◽  
Stephen B. Ferguson ◽  
Lesley A. Stolz ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Active Site ◽  
Cyclophilin A ◽  
Prolyl Isomerase ◽  
Peptidyl Prolyl Isomerase ◽  
Isomerase Activity ◽  
Active Site Mutants ◽  
Calcineurin Inhibition

scholarly journals FKBP51, a novel T-cell-specific immunophilin capable of calcineurin inhibition.

1995 ◽  
Vol 15 (8) ◽  
pp. 4395-4402 ◽  
Author(s):  
G Baughman ◽  
G J Wiederrecht ◽  
N F Campbell ◽  
M M Martin ◽  
S Bourgeois
Keyword(s):  
T Cells ◽  
Cyclosporin A ◽  
Phosphatase Activity ◽  
Immunosuppressive Drugs ◽  
Drug Binding ◽  
Prolyl Isomerase ◽  
Peptidyl Prolyl Isomerase ◽  
Isomerase Activity ◽  
Calcineurin Phosphatase ◽  
Calcineurin Inhibition

The immunosuppressive drugs FK506 and cyclosporin A block T-lymphocyte proliferation by inhibiting calcineurin, a critical signaling molecule for activation. Multiple intracellular receptors (immunophilins) for these drugs that specifically bind either FK506 and rapamycin (FK506-binding proteins [FKBPs]) or cyclosporin A (cyclophilins) have been identified. We report the cloning and characterization of a new 51-kDa member of the FKBP family from murine T cells. The novel immunophilin, FKBP51, is distinct from the previously isolated and sequenced 52-kDa murine FKBP, demonstrating 53% identity overall. Importantly, Western blot (immunoblot) analysis showed that unlike all other FKBPs characterized to date, FKBP51 expression was largely restricted to T cells. Drug binding to recombinant FKBP51 was demonstrated by inhibition of peptidyl prolyl isomerase activity. As judged from peptidyl prolyl isomerase activity, FKBP51 had a slightly higher affinity for rapamycin than for FK520, an FK506 analog. FKBP51, when complexed with FK520, was capable of inhibiting calcineurin phosphatase activity in an in vitro assay system. Inhibition of calcineurin phosphatase activity has been implicated both in the mechanism of immunosuppression and in the observed toxic side effects of FK506 in nonlymphoid cells. Identification of a new FKBP that can mediate calcineurin inhibition and is restricted in its expression to T cells suggests that new immunosuppressive drugs may be identified that, by virtue of their specific interaction with FKBP51, would be targeted in their site of action.

Immunophilin AtFKBP13 Sustains All Peptidyl−Prolyl Isomerase Activity in the Thylakoid Lumen fromArabidopsis thalianaDeficient in AtCYP20-2†

Biochemistry ◽  
2007 ◽  
Vol 46 (33) ◽  
pp. 9432-9442 ◽  
Author(s):  
Anna Edvardsson ◽  
Alexey Shapiguzov ◽  
Ulrika A. Petersson ◽  
Wolfgang P. Schröder ◽  
Alexander V. Vener
Keyword(s):  
Prolyl Isomerase ◽  
Peptidyl Prolyl Isomerase ◽  
Thylakoid Lumen ◽  
Isomerase Activity

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

FEBS Letters ◽  
2003 ◽  
Vol 542 (1-3) ◽  
pp. 137-141 ◽  
Author(s):  
Anna Edvardsson ◽  
Said Eshaghi ◽  
Alexander V Vener ◽  
Bertil Andersson
Keyword(s):  
Prolyl Isomerase ◽  
Peptidyl Prolyl Isomerase ◽  
Thylakoid Lumen ◽  
Isomerase Activity

scholarly journals Cyclophilin A Peptidyl-Prolyl Isomerase Activity Promotes Zpr1 Nuclear Export

2002 ◽  
Vol 22 (20) ◽  
pp. 6993-7003 ◽  
Author(s):  
Husam Ansari ◽  
Giampaolo Greco ◽  
Jeremy Luban
Keyword(s):  
Nuclear Export ◽  
Biological Function ◽  
Zinc Finger Protein ◽  
Cyclophilin A ◽  
Kinetic Studies ◽  
Wild Type ◽  
Prolyl Isomerase ◽  
Ppiase Activity ◽  
Peptidyl Prolyl Isomerase ◽  
Isomerase Activity

ABSTRACT The peptidyl-prolyl isomerase (PPIase) cyclophilin A (Cpr1p) is conserved from eubacteria to mammals, yet its biological function has resisted elucidation. Unable to identify a phenotype that is suggestive of Cpr1p's function in a cpr1Δ Saccharomyces cerevisiae strain, we screened for CPR1-dependent strains. In all cases, dependence was conferred by mutations in ZPR1, a gene encoding an essential zinc finger protein. CPR1 dependence was suppressed by overexpression of EF1α (a translation factor that binds Zpr1p), Cpr6p (another cyclophilin), or Fpr1p (a structurally unrelated PPIase). Suppression by a panel of cyclophilin A mutants correlated with PPIase activity, confirming the relevance of this activity in CPR1-dependent strains. In CPR1 + cells, wild-type Zpr1p was distributed equally between the nucleus and cytoplasm. In contrast, proteins encoded by CPR1-dependent alleles of ZPR1 accumulated in the nucleus, as did wild-type Zpr1p in cpr1Δ cells. Transport kinetic studies indicated that nuclear export of Zpr1p was defective in cpr1Δ cells, and rescue of this defect correlated with PPIase activity. Our results demonstrate a functional interaction between Cpr1p, Zpr1p, and EF1α, a role for Cpr1p in Zpr1p nuclear export, and a biological function for Cpr1p PPIase activity.

scholarly journals Noncatalytic Role of the FKBP52 Peptidyl-Prolyl Isomerase Domain in the Regulation of Steroid Hormone Signaling

2007 ◽  
Vol 27 (24) ◽  
pp. 8658-8669 ◽  
Author(s):  
Daniel L. Riggs ◽  
Marc B. Cox ◽  
Heather L. Tardif ◽  
Martin Hessling ◽  
Johannes Buchner ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Hormone Receptors ◽  
Steroid Hormone ◽  
Genetic Selection ◽  
Steroid Hormone Receptors ◽  
Hormone Signaling ◽  
Prolyl Isomerase ◽  
Peptidyl Prolyl Isomerase ◽  
Isomerase Activity ◽  
Steroid Hormone Signaling

ABSTRACT Hormone-dependent transactivation by several of the steroid hormone receptors is potentiated by the Hsp90-associated cochaperone FKBP52, although not by the closely related FKBP51. Here we analyze the mechanisms of potentiation and the functional differences between FKBP51 and FKBP52. While both have peptidyl-prolyl isomerase activity, this is not required for potentiation, as mutations abolishing isomerase activity did not affect potentiation. Genetic selection in Saccharomyces cerevisiae for gain of potentiation activity in a library of randomly mutated FKBP51 genes identified a single residue at position 119 in the N-terminal FK1 domain as being a critical difference between these two proteins. In both the yeast model and mammalian cells, the FKBP51 mutation L119P, which is located in a hairpin loop overhanging the catalytic pocket and introduces the proline found in FKBP52, conferred significant potentiation activity, whereas the converse P119L mutation in FKBP52 decreased potentiation. A second residue in this loop, A116, also influences potentiation levels; in fact, the FKBP51-A116V L119P double mutant potentiated hormone signaling as well as wild-type FKBP52 did. These results suggest that the FK1 domain, and in particular the loop overhanging the catalytic pocket, is critically involved in receptor interactions and receptor activity.

scholarly journals Cyclophilin40 isomerase activity is regulated by a temperature-dependent allosteric interaction with Hsp90

2015 ◽  
Vol 35 (5) ◽  
Author(s):  
Elizabeth A. Blackburn ◽  
Martin A. Wear ◽  
Vivian Landré ◽  
Vikram Narayan ◽  
Jia Ning ◽  
...  
Keyword(s):  
Heat Shock Protein 90 ◽  
Prolyl Isomerase ◽  
Temperature Dependent ◽  
Ppiase Activity ◽  
Peptidyl Prolyl Isomerase ◽  
Isomerase Activity ◽  
C Terminus ◽  
Hsp 90 ◽  
Cyclophilin 40 ◽  
Tpr Domain

Binding the C-terminus of heat shock protein 90 (Hsp 90) to the tetratricopeptide repeat (TPR) domain of cyclophilin 40 (Cyp40) allosterically changes the dynamics of the cyclophilin-active site and reduces peptidyl-prolyl isomerase (PPIase) activity.

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