Genomes and Genes
tacrolimus binding proteins
Summary: A family of immunophilin proteins that bind to the immunosuppressive drugs TACROLIMUS (also known as FK506) and SIROLIMUS. EC 5.2.1.-
- Binder E. The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology. 2009;34 Suppl 1:S186-95 pubmed publisher..In addition, they are also associated with faster response to antidepressant treatment. FKBP5 might thus be an interesting therapeutic target for the prevention and treatment of stress-related psychiatric disorders. ..
- Granzin J, Eckhoff A, Weiergräber O. Crystal structure of a multi-domain immunophilin from Arabidopsis thaliana: a paradigm for regulation of plant ABC transporters. J Mol Biol. 2006;364:799-809 pubmed..The resulting models provide a structural background for further investigation of the unique biological properties of this protein...
- Meiri D, Tazat K, Cohen Peer R, Farchi Pisanty O, Aviezer Hagai K, Avni A, et al. Involvement of Arabidopsis ROF2 (FKBP65) in thermotolerance. Plant Mol Biol. 2010;72:191-203 pubmed publisher..Transient expression of ROF2 together with ROF1 repressed transcription of small HSPs. A model describing the mode of action of ROF2 as a heat stress modulator which functions in negative feedback regulation of HsfA2 is proposed. ..
- Gerard M, Deleersnijder A, Daniëls V, Schreurs S, Munck S, Reumers V, et al. Inhibition of FK506 binding proteins reduces alpha-synuclein aggregation and Parkinson's disease-like pathology. J Neurosci. 2010;30:2454-63 pubmed publisher..Our data explain previously described neuroregenerative and neuroprotective effects of immunophilin ligands and validate FKBPs as a novel drug target for the causative treatment of PD. ..
- Alanay Y, Avaygan H, Camacho N, Utine G, Boduroglu K, Aktas D, et al. Mutations in the gene encoding the RER protein FKBP65 cause autosomal-recessive osteogenesis imperfecta. Am J Hum Genet. 2010;86:551-9 pubmed publisher..Further, we determined that FKBP10 mutations affect type I procollagen secretion. These findings identify a previously unrecognized mechanism in the pathogenesis of OI. ..
- Chambraud B, Sardin E, Giustiniani J, Dounane O, Schumacher M, Goedert M, et al. A role for FKBP52 in Tau protein function. Proc Natl Acad Sci U S A. 2010;107:2658-63 pubmed publisher..Taken together, these findings indicate a role for FKBP52 in Tau function and may help to decipher and modulate the events involved in Tau-induced neurodegeneration. ..
- Roy A, Gorodetsky E, Yuan Q, Goldman D, ENOCH M. Interaction of FKBP5, a stress-related gene, with childhood trauma increases the risk for attempting suicide. Neuropsychopharmacology. 2010;35:1674-83 pubmed publisher..These data suggest that childhood trauma and variants of the FKBP5 gene may interact to increase the risk for attempting suicide. ..
- Galfré E, Pitt S, Venturi E, Sitsapesan M, Zaccai N, Tsaneva Atanasova K, et al. FKBP12 activates the cardiac ryanodine receptor Ca2+-release channel and is antagonised by FKBP12.6. PLoS ONE. 2012;7:e31956 pubmed publisher..In heart failure, it is possible that an alteration in the dual regulation of RyR2 by FKBP12 and FKBP12.6 may occur. This could contribute towards a higher RyR2 open probability, 'leaky' RyR2 channels and Ca(2+)-dependent arrhythmias. ..
- Wang Y, Kirschner A, Fabian A, Gopalakrishnan R, Kress C, Hoogeland B, et al. Increasing the efficiency of ligands for FK506-binding protein 51 by conformational control. J Med Chem. 2013;56:3922-35 pubmed publisher..Our work exemplifies how atom-efficient ligands can be achieved by careful conformational control even in very open and thus difficult binding sites such as FKBP51. ..
- Galigniana N, Ballmer L, Toneatto J, Erlejman A, Lagadari M, Galigniana M. Regulation of the glucocorticoid response to stress-related disorders by the Hsp90-binding immunophilin FKBP51. J Neurochem. 2012;122:4-18 pubmed publisher..In this review, we discuss different aspects of the role of FKBP51 in such steroid receptor function and the impact of genetic variants of the immunophilin on the dysregulation of the stress response. ..
- Blayney L, Jones J, Griffiths J, Lai F. A mechanism of ryanodine receptor modulation by FKBP12/12.6, protein kinase A, and K201. Cardiovasc Res. 2010;85:68-78 pubmed publisher..6 binding. K201 stabilized the conformation, whereas phosphorylation facilitated a subsequent molecular event that might increase the rate of an open/closed conformational transition...
- Ni L, Yang C, Gioeli D, Frierson H, Toft D, Paschal B. FKBP51 promotes assembly of the Hsp90 chaperone complex and regulates androgen receptor signaling in prostate cancer cells. Mol Cell Biol. 2010;30:1243-53 pubmed publisher..Because the superchaperone complex plays a critical role in determining the ligand-binding competence and transcription function of AR, it provides an attractive target for inhibiting AR activity in prostate cancer cells. ..
- Yao Y, Liang Y, Huang H, Yang W. FKBPs in chromatin modification and cancer. Curr Opin Pharmacol. 2011;11:301-7 pubmed publisher..Therefore, elucidation of the nuclear functions of FKBPs will help researchers and clinicians better understand how immunosuppressants work as anticancer drugs, which might in turn lead to novel designs of cancer therapy. ..
- Cheng Y, Dai D, Dai Y. Stress-induced cardiac insufficiency relating to abnormal leptin and FKBP12.6 is ameliorated by CPU0213, an endothelin receptor antagonist, which is not affected by the CYP3A suppressing effect of erythromycin. J Pharm Pharmacol. 2009;61:569-76 pubmed publisher..CPU0213 improved isoprenaline-induced cardiomyopathy by modulating ETA, leptin and FKBP12.6. However, erythromycin increased plasma levels but did not change its effects. ..
- Kozany C, März A, Kress C, Hausch F. Fluorescent probes to characterise FK506-binding proteins. Chembiochem. 2009;10:1402-10 pubmed publisher..This probe showed moderate affinity for the FK1 domains of FKBP51 (177 nM) and FKBP52 (469 nM) and allowed a highly robust, optimized, miniaturized assay (Z'>0.7) sufficient for high-throughput screening of large compound libraries. ..
- Gopalakrishnan R, Kozany C, Gaali S, Kress C, Hoogeland B, Bracher A, et al. Evaluation of synthetic FK506 analogues as ligands for the FK506-binding proteins 51 and 52. J Med Chem. 2012;55:4114-22 pubmed publisher..The interaction with FKBPs was found to be surprisingly tolerant to the stereochemistry of the attached cyclohexyl substituents. The molecular basis for this tolerance was elucidated by X-ray cocrystallography. ..
- Touma C, Gassen N, Herrmann L, Cheung Flynn J, Büll D, Ionescu I, et al. FK506 binding protein 5 shapes stress responsiveness: modulation of neuroendocrine reactivity and coping behavior. Biol Psychiatry. 2011;70:928-36 pubmed publisher..This lends strong support to the concept emerging from human studies of FKBP5 as important factor governing gene-environment interactions relevant for the etiology of affective disorders. ..
- Periyasamy S, Hinds T, Shemshedini L, Shou W, Sanchez E. FKBP51 and Cyp40 are positive regulators of androgen-dependent prostate cancer cell growth and the targets of FK506 and cyclosporin A. Oncogene. 2010;29:1691-701 pubmed publisher..These proteins and their cognate ligands thus provide new strategies in the treatment of PCa. ..
- Ellsworth K, Moon I, Eckloff B, Fridley B, Jenkins G, Batzler A, et al. FKBP5 genetic variation: association with selective serotonin reuptake inhibitor treatment outcomes in major depressive disorder. Pharmacogenet Genomics. 2013;23:156-66 pubmed publisher..This comprehensive FKBP5 sequence study provides insight into the role of common genetic polymorphisms that might influence SSRI treatment outcomes in major depressive disorder patients. ..
- Zoldak G, Schmid F. Cooperation of the prolyl isomerase and chaperone activities of the protein folding catalyst SlyD. J Mol Biol. 2011;406:176-94 pubmed publisher..Protein molecules that left the prolyl isomerase site with an incorrect prolyl isomer can rapidly be re-bound by the chaperone domain because the association rate is very high as well. ..
- Bracher A, Kozany C, Thost A, Hausch F. Structural characterization of the PPIase domain of FKBP51, a cochaperone of human Hsp90. Acta Crystallogr D Biol Crystallogr. 2011;67:549-59 pubmed publisher..These structures provide a detailed picture of the drug-binding domain of FKBP51 and the molecular binding mode of its ligand as a starting point for the rational design of improved inhibitors. ..
- Gollan P, Bhave M. Genome-wide analysis of genes encoding FK506-binding proteins in rice. Plant Mol Biol. 2010;72:1-16 pubmed publisher..The rice FKBP family appears to have evolved by duplications of FKBP genes, which may be a strategy for increased stress tolerance. ..
- Jinwal U, Koren J, Borysov S, Schmid A, Abisambra J, Blair L, et al. The Hsp90 cochaperone, FKBP51, increases Tau stability and polymerizes microtubules. J Neurosci. 2010;30:591-9 pubmed publisher..Based on these new findings, we propose that FKBP51 can use the Hsp90 complex to isomerize tau, altering its phosphorylation pattern and stabilizing microtubules. ..
- Brent D, Melhem N, Ferrell R, Emslie G, Wagner K, Ryan N, et al. Association of FKBP5 polymorphisms with suicidal events in the Treatment of Resistant Depression in Adolescents (TORDIA) study. Am J Psychiatry. 2010;167:190-7 pubmed publisher..The small number of events and lack of a placebo condition make these results preliminary. Replication with a larger sample and a placebo condition is needed to assess whether these events are related to treatment. ..
- Blackburn E, Walkinshaw M. Targeting FKBP isoforms with small-molecule ligands. Curr Opin Pharmacol. 2011;11:365-71 pubmed publisher..This observation opens the way to the design of isoform specific inhibitors. ..
- O Leary J, Dharia S, Blair L, Brady S, Johnson A, Peters M, et al. A new anti-depressive strategy for the elderly: ablation of FKBP5/FKBP51. PLoS ONE. 2011;6:e24840 pubmed publisher..Age-dependent anxiety was also modulated by FKBP5 deletion. Therefore, drug discovery efforts focused on depleting FKBP51 levels may yield novel antidepressant therapies. ..
- Komatsu T, Kukelyansky I, McCaffery J, Ueno T, Varela L, Inoue T. Organelle-specific, rapid induction of molecular activities and membrane tethering. Nat Methods. 2010;7:206-8 pubmed publisher..Innovative techniques to rapidly perturb molecular activities and organelle-organelle communications at precise locations and timing will provide powerful strategies to dissect spatiotemporally complex biological processes. ..
- Paakinaho V, Makkonen H, Jääskeläinen T, Palvimo J. Glucocorticoid receptor activates poised FKBP51 locus through long-distance interactions. Mol Endocrinol. 2010;24:511-25 pubmed publisher..Taken together, these results indicate that the holo-GR is capable of activating transcription and evoking changes in chromatin structure through distant-acting enhancers. ..
- Iwamoto M, Bjorklund T, Lundberg C, Kirik D, Wandless T. A general chemical method to regulate protein stability in the mammalian central nervous system. Chem Biol. 2010;17:981-8 pubmed publisher..The ability of TMP to cross the blood-brain barrier enables the tunable regulation of proteins expressed in the mammalian central nervous system. ..
- De Leon J, Iwai A, Feau C, Garcia Y, Balsiger H, Storer C, et al. Targeting the regulation of androgen receptor signaling by the heat shock protein 90 cochaperone FKBP52 in prostate cancer cells. Proc Natl Acad Sci U S A. 2011;108:11878-83 pubmed publisher..Assays in early and late stage human prostate cancer cells demonstrated that MJC13 inhibits AR-dependent gene expression and androgen-stimulated prostate cancer cell proliferation. ..
- Bracher A, Kozany C, Hähle A, Wild P, Zacharias M, Hausch F. Crystal structures of the free and ligand-bound FK1-FK2 domain segment of FKBP52 reveal a flexible inter-domain hinge. J Mol Biol. 2013;425:4134-44 pubmed publisher..The observed subtle differences provide crucial insights for the rational design of ligands with improved selectivity for FKBP52. ..
- Robida A, Kerppola T. Bimolecular fluorescence complementation analysis of inducible protein interactions: effects of factors affecting protein folding on fluorescent protein fragment association. J Mol Biol. 2009;394:391-409 pubmed publisher..Conditional BiFC complex formation depends on the folding efficiencies of fluorescent protein fragments and can be affected by the cellular protein folding environment. ..
- Unger T, Dym O, Albeck S, Jacobovitch Y, Bernehim R, Marom D, et al. Crystal structure of the three FK506 binding protein domains of wheat FKBP73: evidence for a unique wFK73_2 domain. J Struct Funct Genomics. 2010;11:113-23 pubmed publisher..We suggest that the existence of FKBPs with three FK domains offers additional interactive options for these plant proteins enlarging the overall regulatory functions of these proteins. ..
- Seidler T, Teucher N, Hellenkamp K, Unsöld B, Grebe C, Kramps P, et al. Limitations of FKBP12.6-directed treatment strategies for maladaptive cardiac remodeling and heart failure. J Mol Cell Cardiol. 2011;50:33-42 pubmed publisher..6-RyR2 reconstitution in heart failure and maladaptive remodeling, although RyR2 Ca leak can be reduced. ..
- Romano S, Di Pace A, Sorrentino A, Bisogni R, Sivero L, Romano M. FK506 binding proteins as targets in anticancer therapy. Anticancer Agents Med Chem. 2010;10:651-6 pubmed..anticancer activity. In this review, we focus on the role of FKBP members in apoptosis control and summarize the data on the antitumor effect of selective targeting of FKBP. ..
- Xie P, Kranzler H, Poling J, Stein M, Anton R, Farrer L, et al. Interaction of FKBP5 with childhood adversity on risk for post-traumatic stress disorder. Neuropsychopharmacology. 2010;35:1684-92 pubmed publisher..This study provides further evidence of a gene x environment effect of FKBP5 and childhood abuse on the risk for PTSD in AAs. Further study is required in other populations. ..
- Romano S, D Angelillo A, Pacelli R, Staibano S, de Luna E, Bisogni R, et al. Role of FK506-binding protein 51 in the control of apoptosis of irradiated melanoma cells. Cell Death Differ. 2010;17:145-57 pubmed publisher..Finally, we provide evidence that FKBP51 targeting radiosensitizes cancer stem/initiating cells. In conclusion, our study identifies a possible molecular target for radiosensitizing therapeutic strategies against malignant melanoma. ..
- Gopalakrishnan R, Kozany C, Wang Y, Schneider S, Hoogeland B, Bracher A, et al. Exploration of pipecolate sulfonamides as binders of the FK506-binding proteins 51 and 52. J Med Chem. 2012;55:4123-31 pubmed publisher..A focused solid support-based synthesis protocol was developed, which led to ligands with submicromolar affinity for FKBP51 and FKBP52. The molecular binding mode for one sulfonamide analogue was confirmed by X-ray crystallography. ..
- Romano S, Sorrentino A, Di Pace A, Nappo G, Mercogliano C, Romano M. The emerging role of large immunophilin FK506 binding protein 51 in cancer. Curr Med Chem. 2011;18:5424-9 pubmed..The aim of this article is to review the functions of FKBP51, especially in view of the recent findings that this protein is a potential oncogene when deregulated and a candidate target for signaling therapies against cancer. ..
- Anderson J, HERNANDEZ G, LeMaster D. Assessing the chemical accuracy of protein structures via peptide acidity. Biophys Chem. 2013;171:63-75 pubmed publisher..However, the more recent RECOORD refinement study of CI2 yielded predictions comparable to the X-ray and homology model-based analyses. ..
- Echeverria P, Mazaira G, Erlejman A, Gomez Sanchez C, Piwien Pilipuk G, Galigniana M. Nuclear import of the glucocorticoid receptor-hsp90 complex through the nuclear pore complex is mediated by its interaction with Nup62 and importin beta. Mol Cell Biol. 2009;29:4788-97 pubmed publisher..Importantly, GR cross-linked to the hsp90 heterocomplex was able to translocate to the nucleus in digitonin-permeabilized cells treated with steroid, suggesting that GR could pass through the pore in its untransformed state. ..
- Scharf S, Liebl C, Binder E, Schmidt M, Muller M. Expression and regulation of the Fkbp5 gene in the adult mouse brain. PLoS ONE. 2011;6:e16883 pubmed publisher..In summary, we were able to give an overview of the basal expression of fkbp5 mRNA as well as to extend the findings of induction of Fkbp5 and its regulatory influence on GR sensitivity from peripheral blood to the brain. ..
- Gallo L, Lagadari M, Piwien Pilipuk G, Galigniana M. The 90-kDa heat-shock protein (Hsp90)-binding immunophilin FKBP51 is a mitochondrial protein that translocates to the nucleus to protect cells against oxidative stress. J Biol Chem. 2011;286:30152-60 pubmed publisher..In summary, this is the first demonstration that FKBP51 is a major mitochondrial factor that undergoes nuclear-mitochondrial shuttling, an observation that may be related to antiapoptotic mechanisms triggered during the stress response. ..
- Cereghetti G, Costa V, Scorrano L. Inhibition of Drp1-dependent mitochondrial fragmentation and apoptosis by a polypeptide antagonist of calcineurin. Cell Death Differ. 2010;17:1785-94 pubmed publisher..Thus, PPD1 is a novel inhibitor of apoptosis that elucidates the function of calcineurin-dependent mitochondrial fragmentation in the amplification of cell death. ..
- Schmidt M, Paez Pereda M, Holsboer F, Hausch F. The prospect of FKBP51 as a drug target. ChemMedChem. 2012;7:1351-9 pubmed publisher..In summary, FKBP51 has emerged as a promising new drug target for stress-related disorders that should be amenable to drug discovery. ..
- Chun E, Lee H, Bang B, Kim T, Lee S, Kim J, et al. Dexamethasone-induced FKBP51 expression in peripheral blood mononuclear cells could play a role in predicting the response of asthmatics to treatment with corticosteroids. J Clin Immunol. 2011;31:122-7 pubmed publisher..Dexamethasone-induced FKBP51 expression in PBMCs may be a reliable and practical biomarker in predicting the response to CSs in asthmatics. ..
- Zobel A, Schuhmacher A, Jessen F, Hofels S, von Widdern O, Metten M, et al. DNA sequence variants of the FKBP5 gene are associated with unipolar depression. Int J Neuropsychopharmacol. 2010;13:649-60 pubmed publisher..Furthermore, several of the investigated SNPs were associated with the disease status and the intermediate phenotype of hippocampal volume. ..
- Li L, Lou Z, Wang L. The role of FKBP5 in cancer aetiology and chemoresistance. Br J Cancer. 2011;104:19-23 pubmed publisher..In this review, we will focus on the recently discovered role of FKBP5 in cancer aetiology and response to antineoplastic therapy. ..
- Oyama M, Chittur S, Reynolds C. Decreased triadin and increased calstabin2 expression in Great Danes with dilated cardiomyopathy. J Vet Intern Med. 2009;23:1014-9 pubmed publisher..These changes likely affect Ca2+ flux within cardiac cells and may contribute to the pathophysiology of disease. Microarray-based analysis identifies calstabin2, triadin, and RyR2 function as targets of future study. ..
- Tatro E, Everall I, Kaul M, Achim C. Modulation of glucocorticoid receptor nuclear translocation in neurons by immunophilins FKBP51 and FKBP52: implications for major depressive disorder. Brain Res. 2009;1286:1-12 pubmed publisher..We propose that immunophilins are modulators of the cortisol-HPA axis response to stress and related chronic brain disorders. ..
- Pei H, Li L, Fridley B, Jenkins G, Kalari K, LINGLE W, et al. FKBP51 affects cancer cell response to chemotherapy by negatively regulating Akt. Cancer Cell. 2009;16:259-66 pubmed publisher..Overall, our findings identify FKBP51 as a negative regulator of the Akt pathway, with potentially important implications for cancer etiology and response to chemotherapy. ..
- Romano S, Mallardo M, Romano M. FKBP51 and the NF-?B regulatory pathway in cancer. Curr Opin Pharmacol. 2011;11:288-93 pubmed publisher..This article is an overview of the causes of aberrant NF-?B regulation in cancer and highlights recent papers that implicate FKBP51 in such deregulation. ..
- Budiman C, Tadokoro T, Angkawidjaja C, Koga Y, Kanaya S. Role of polar and nonpolar residues at the active site for PPIase activity of FKBP22 from Shewanella sp. SIB1. FEBS J. 2012;279:976-86 pubmed publisher..However, the mutations of Trp157 to Phe or Phe197 to Leu greatly decrease the enzymatic activity, suggesting that the shape of the substrate-binding cavity is also important for enzymatic activity. ..
- Pelleymounter L, Moon I, Johnson J, Laederach A, Halvorsen M, Eckloff B, et al. A novel application of pattern recognition for accurate SNP and indel discovery from high-throughput data: targeted resequencing of the glucocorticoid receptor co-chaperone FKBP5 in a Caucasian population. Mol Genet Metab. 2011;104:457-69 pubmed publisher..Finally we show how our discovery of rare variants may change current conceptions of evolution at this locus. ..
- Ingelsson B, Shapiguzov A, Kieselbach T, Vener A. Peptidyl-prolyl isomerase activity in chloroplast thylakoid lumen is a dispensable function of immunophilins in Arabidopsis thaliana. Plant Cell Physiol. 2009;50:1801-14 pubmed publisher..It is concluded that cellular functions of immunophilins in the thylakoid lumen of chloroplasts are not related to their PPIase capacity and should be investigated beyond this enzymatic activity. ..
- Guo T, Cornea R, Huke S, Camors E, Yang Y, Picht E, et al. Kinetics of FKBP12.6 binding to ryanodine receptors in permeabilized cardiac myocytes and effects on Ca sparks. Circ Res. 2010;106:1743-52 pubmed publisher..6-RyR2 association and activate RyR2. However, the function of FKBP12.6/12 and role of PKA phosphorylation in cardiac myocytes are controversial...
- Jiang D, Jones P, Davis D, Gow R, Green M, Birnie D, et al. Characterization of a novel mutation in the cardiac ryanodine receptor that results in catecholaminergic polymorphic ventricular tachycardia. Channels (Austin). 2010;4:302-10 pubmed..6. These observations strengthen the notion that enhanced SOICR, but not altered FKBP12.6 binding, is a common mechanism by which RyR2 mutations cause arrhythmias. ..
- Tatro E, Nguyen T, Bousman C, Masliah E, Grant I, Atkinson J, et al. Correlation of major depressive disorder symptoms with FKBP5 but not FKBP4 expression in human immunodeficiency virus-infected individuals. J Neurovirol. 2010;16:399-404 pubmed publisher..Change in FKBP4 expression did not correlate with changes in clinical or depression measurements. Higher FKBP5 expression correlated with greater symptom change for GG carriers of rs3800373. ..
- Mustafi S, Chen H, Li H, LeMaster D, HERNANDEZ G. Analysing the visible conformational substates of the FK506-binding protein FKBP12. Biochem J. 2013;453:371-80 pubmed publisher..The K44V mutation selectively reduces the line-broadening in the 40's loop, verifying that at least three distinct conformational transitions underlie the line-broadening processes of FKBP12. ..
- Hartmann J, Wagner K, Liebl C, Scharf S, Wang X, Wolf M, et al. The involvement of FK506-binding protein 51 (FKBP5) in the behavioral and neuroendocrine effects of chronic social defeat stress. Neuropharmacology. 2012;62:332-9 pubmed publisher..These results suggest an enhanced negative glucocorticoid feedback within the HPA axis of 51KO mice, possibly modulated by an increased sensitivity of the GR. This article is part of a Special Issue entitled 'Anxiety and Depression'. ..
- Lee R, Tamashiro K, Yang X, Purcell R, Harvey A, Willour V, et al. Chronic corticosterone exposure increases expression and decreases deoxyribonucleic acid methylation of Fkbp5 in mice. Endocrinology. 2010;151:4332-43 pubmed publisher..In the CORT-treated mice, we also observed changes in blood DNAm in Fkbp5. Our results suggest DNAm plays a role in mediating effects of glucocorticoid exposure on Fkbp5 function, with potential consequences for behavior. ..