The immunophilins

Wiederrecht, Gregory; Etzkorn, Felicia A.

doi:10.1007/bf02171737

Cited by 45 publications

(34 citation statements)

References 205 publications

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“…Among these FKBPs, 1 FKBP12 is the most abundant and is involved in mediating the immunosuppressive action of FK506 in T lymphocytes. All of the known FKBP family members display cis-trans peptidyl-prolyl isomerase (PPIase) activity that is inhibited by FK506 and a structurally related compound, rapamycin (1). However, neither the immunosuppressive nor toxic side effects (including severe neuro-and nephrotoxicity) associated with FK506 therapy result from the inhibition of PPIase activity.…”

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confidence: 99%

“…: 615-322-2132; Fax: 615-343-6833; E-mail: fleiscs@ctrvax.vanderbilt.edu. 1 The abbreviations used are: FKBP, FK506-binding protein; FKBP12, a 12-kDa FKBP; FKBP12.6, isoform of FKBP with slightly slower mobility than FKBP12; PPIase, cis-trans peptidyl-prolyl isomerase; RyR-1 and RyR-2, ryanodine receptor isoform 1 from skeletal muscle and isoform 2 from heart, respectively; SkM, skeletal muscle; SR, sarcoplasmic reticulum; TC, terminal cisternae of SR; CSR, cardiac SR; CRC, calcium release channel; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate; HEDTA, N-(2-hydroxyethyl)-ethylenediamine-N,NЈ,NЉ-triacetic acid; GST/FKBP12 and GST/ FKBP12.6, fusion proteins of glutathione S-transferase with FKBP12 FKBP12 in skeletal muscle cytosol is about 3 M (10). Thus, given the concentration and temperature dependence for exchange, our studies indicate that FKBP12, bound to the SkM CRC, is in rapid equilibrium with the myoplasmic pool of FKBP12.…”

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Selective Binding of FKBP12.6 by the Cardiac Ryanodine Receptor

Timerman

Onoue

Xin

et al. 1996

Journal of Biological Chemistry

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257

286

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The calcium release channels (CRC)/ryanodine receptors of skeletal (Sk) and cardiac (C) muscle sarcoplasmic reticulum (SR) are hetero-oligomeric complexes with the structural formulas (ryanodine recepter (RyR)1 protomer) 4 (FKBP12) 4 and (RyR2 protomer) 4 (FKBP12.6) 4 , respectively, where FKBP12 and FKBP12.6 are isoforms of the 12-kDa receptor for the immunosuppressant drug FK506. The sequence similarity between the RyR protomers and FKBP12 isoforms is 63 and 85%, respectively. Using 35 S-labeled FKBP12 and 35 S-labeled FKBP12.6 as probes to study the interaction with CRC, we find that: 1) analogous to its action in skeletal muscle sarcoplasmic reticulum (SkMSR), FK506 (or analog FK590) dissociates FKBP12.6 from CSR; 2) both FKBP isoforms bind to FKBP-stripped SkMSR and exchange with endogenously bound FKBP12 of SkMSR; and 3) by contrast, only FKBP12.6 exchanges with endogenously bound FKBP12.6 or rebinds to FKBP-stripped CSR. This selective binding appears to explain why the cardiac CRC is isolated as a complex with FKBP12.6, whereas the skeletal muscle CRC is isolated as a complex with FKBP12, although only FKBP12 is detectable in the myoplasm of both muscle types. Also, in contrast to the activation of the channel by removal of FKBP from skeletal muscle, no activation is detected in CRC activity in FKBPstripped CSR. This differential action of FKBP may reflect a fundamental difference in the modulation of excitation-contraction coupling in heart versus skeletal muscle.FK506 is a potent immunosuppressive drug that binds to a family of related intracellular receptors termed FK506-binding proteins, varying in size from 12 to 54 kDa. Among these FKBPs, 1 FKBP12 is the most abundant and is involved in mediating the immunosuppressive action of FK506 in T lymphocytes. All of the known FKBP family members display cis-trans peptidyl-prolyl isomerase (PPIase) activity that is inhibited by FK506 and a structurally related compound, rapamycin (1). However, neither the immunosuppressive nor toxic side effects (including severe neuro-and nephrotoxicity) associated with FK506 therapy result from the inhibition of PPIase activity. Rather, the action of FK506 results from the specific inhibition of calcineurin by the FKBP12⅐drug complex. Calcineurin is a calcium-dependent protein phosphatase involved in the activation of T-lymphocytes (2). FKBP12 is a mere bystander protein during T-cell activation that becomes involved in blocking activation after it binds FK506. To date, the only physiological function directly associated with FKBP12 is its tight binding to (3, 4) and modulation of the ryanodine receptor (RyR-1) or calcium release channel of skeletal muscle SR (5-10). The purified SkM CRC 2 isolated from the CHAPS-solubilized TC is a hetero-oligomeric complex, with the structural formula of (RyR-1 protomer) 4 (FKBP12) 4 (5). Both FK506 and rapamycin bind to and dissociate FKBP12 from the SkM CRC (5). Both the native and FKBP-stripped CRCs have similar unitary conductance and sensitivity to ruthenium red (6). However, in co...

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confidence: 99%

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confidence: 99%

Selective Binding of FKBP12.6 by the Cardiac Ryanodine Receptor

Timerman

Onoue

Xin

et al. 1996

Journal of Biological Chemistry

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257

286

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“…The term FKBP refers to any protein which binds both FK506 and rapamycin immunosuppressive compounds. Several FKBPs have been isolated to date from a broad range of organisms, and they are named according to their molecular masses (13,42). These proteins also have peptidyl-prolyl cis-trans isomerase (rotamase) activity.…”

Section: Resultsmentioning

confidence: 99%

“…Two immunophilin families can be distinguished: cyclophilins and FKBPs. The FKBPs, represented by the well-studied FKBP12, bind the immunosuppressants FK506 and rapamycin, whereas the cyclophilins bind cyclosporin A (42). Although the two families do not have structural or sequence homology, all immunophilins identified to date exhibit peptidyl-prolyl cis-trans isomerase (rotamase) activity.…”

Section: Discussionmentioning

confidence: 99%

Mutation in theArabidopsis PASTICCINO1Gene, Which Encodes a New FK506-Binding Protein-Like Protein, Has a Dramatic Effect on Plant Development

Vittorioso

Cowling

Faure

et al. 1998

Molecular and Cellular Biology

123

105

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The pasticcino (pas) mutants of Arabidopsis thaliana are a new class of plant developmental mutants; members of this class show ectopic cell proliferation in cotyledons, extra layers of cells in the hypocotyl, and an abnormal apical meristem. This phenotype is correlated with both cell division and cell elongation defects. There are three complementation groups of pas mutants (pas1, pas2, and pas3, with, respectively 2, 1, and 4 alleles). Here we describe in more detail the pas1-1 allele, which was obtained by insertional mutagenesis. The PAS1 gene has been cloned and characterized; it encodes an immunophilin-like protein similar to the p59 FK506-binding protein (FKBP52). PAS1 is characterized by an FKBP-like domain and three tetratricopeptide repeat units. Although the presence of immunophilins in plants has already been demonstrated, the pas1-1 mutant represents the first inactivation of an FKBP-like gene in plants. PAS1 expression is altered in pas1 mutants and in the pas2 and pas3 mutants. The expression of the PAS1 gene is increased in the presence of cytokinins, a class of phytohormones originally discovered because of their ability to stimulate cell division. These results are of particular relevance as they show for the first time that an FKBP-like protein plays an important role in the control of plant development.In flowering plants, morphogenesis depends on the control of the pattern and numbers of cell divisions and on the control of cell elongation. Although there are many examples of controlled patterns of cell division, we still know very little about how local patterns of cell division are established and maintained (30). In Arabidopsis thaliana, the roles of cell division control in the development of the embryo, the shoot, and the root have been extensively studied (reviewed in references 29 and 30). In the last few years, much progress has been made in this field by the isolation of mutants in which single-gene mutations affect specific modes of cell division control. Some of the corresponding genes have been cloned from A. thaliana (SHOOT MERISTEMLESS [STM] and SCARECROW [SCR]) maize (KNOTTED1), and petunia (NO APICAL MERISTEM) (reviewed in reference 30). These genes do not seem to specify components of the cell division machinery, but they are thought to act upstream in the control of cell division. The elements at the interface between genes like STM and SCR and cell cycle regulators, such as cyclins and the CDC genes, are still unknown.The growth and differentiation of higher plants is also greatly dependent on environmental stimuli, such as light and temperature, and on endogenous factors, such as phytohormones. Cytokinins (CKs) were originally discovered because of their ability to promote, along with auxins, plant cell division and organogenesis (reviewed in reference 9). Although this discovery initiated a vast amount of fundamental and applied research on the hormonal control of cell proliferation and regeneration, the mechanisms by which auxins and CKs act and interact at the molecu...

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“…Among the growing family of FKBPs the best characterized member is a 12-kDa isoform, FKBP12 (reviewed in Refs. [1][2][3][4].…”

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confidence: 99%