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ER trapping reveals Golgi enzymes continually revisit the ER through a recycling pathway that controls Golgi organization.
Sengupta P, Satpute-Krishnan P, Seo AY, Burnette DT, Patterson GH, Lippincott-Schwartz J
(2015) Proc Natl Acad Sci U S A 112: E6752-61
MeSH Terms: Animals, COS Cells, Cercopithecus aethiops, Endoplasmic Reticulum, Golgi Apparatus, HeLa Cells, Humans, Mitosis, Phospholipases A2, Calcium-Independent, Sirolimus, Tacrolimus Binding Protein 1A, Tacrolimus Binding Proteins, rab GTP-Binding Proteins
Show Abstract · Added August 25, 2017
Whether Golgi enzymes remain localized within the Golgi or constitutively cycle through the endoplasmic reticulum (ER) is unclear, yet is important for understanding Golgi dependence on the ER. Here, we demonstrate that the previously reported inefficient ER trapping of Golgi enzymes in a rapamycin-based assay results from an artifact involving an endogenous ER-localized 13-kD FK506 binding protein (FKBP13) competing with the FKBP12-tagged Golgi enzyme for binding to an FKBP-rapamycin binding domain (FRB)-tagged ER trap. When we express an FKBP12-tagged ER trap and FRB-tagged Golgi enzymes, conditions precluding such competition, the Golgi enzymes completely redistribute to the ER upon rapamycin treatment. A photoactivatable FRB-Golgi enzyme, highlighted only in the Golgi, likewise redistributes to the ER. These data establish Golgi enzymes constitutively cycle through the ER. Using our trapping scheme, we identify roles of rab6a and calcium-independent phospholipase A2 (iPLA2) in Golgi enzyme recycling, and show that retrograde transport of Golgi membrane underlies Golgi dispersal during microtubule depolymerization and mitosis.
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13 MeSH Terms
A rodent model of traumatic stress induces lasting sleep and quantitative electroencephalographic disturbances.
Nedelcovych MT, Gould RW, Zhan X, Bubser M, Gong X, Grannan M, Thompson AT, Ivarsson M, Lindsley CW, Conn PJ, Jones CK
(2015) ACS Chem Neurosci 6: 485-93
MeSH Terms: Analysis of Variance, Animals, Brain Waves, Corticosterone, Disease Models, Animal, Electroencephalography, Electromyography, Fourier Analysis, Indoles, Male, Neuropeptide Y, RNA, Messenger, Random Allocation, Rats, Rats, Sprague-Dawley, Serotonin, Sleep Wake Disorders, Stress Disorders, Post-Traumatic, Tacrolimus Binding Proteins, Time Factors
Show Abstract · Added February 12, 2015
Hyperarousal and sleep disturbances are common, debilitating symptoms of post-traumatic stress disorder (PTSD). PTSD patients also exhibit abnormalities in quantitative electroencephalography (qEEG) power spectra during wake as well as rapid eye movement (REM) and non-REM (NREM) sleep. Selective serotonin reuptake inhibitors (SSRIs), the first-line pharmacological treatment for PTSD, provide modest remediation of the hyperarousal symptoms in PTSD patients, but have little to no effect on the sleep-wake architecture deficits. Development of novel therapeutics for these sleep-wake architecture deficits is limited by a lack of relevant animal models. Thus, the present study investigated whether single prolonged stress (SPS), a rodent model of traumatic stress, induces PTSD-like sleep-wake and qEEG spectral power abnormalities that correlate with changes in central serotonin (5-HT) and neuropeptide Y (NPY) signaling in rats. Rats were implanted with telemetric recording devices to continuously measure EEG before and after SPS treatment. A second cohort of rats was used to measure SPS-induced changes in plasma corticosterone, 5-HT utilization, and NPY expression in brain regions that comprise the neural fear circuitry. SPS caused sustained dysregulation of NREM and REM sleep, accompanied by state-dependent alterations in qEEG power spectra indicative of cortical hyperarousal. These changes corresponded with acute induction of the corticosterone receptor co-chaperone FK506-binding protein 51 and delayed reductions in 5-HT utilization and NPY expression in the amygdala. SPS represents a preclinical model of PTSD-related sleep-wake and qEEG disturbances with underlying alterations in neurotransmitter systems known to modulate both sleep-wake architecture and the neural fear circuitry.
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20 MeSH Terms
Structure of human peptidyl-prolyl cis-trans isomerase FKBP22 containing two EF-hand motifs.
Boudko SP, Ishikawa Y, Nix J, Chapman MS, Bächinger HP
(2014) Protein Sci 23: 67-75
MeSH Terms: Catalytic Domain, EF Hand Motifs, Ehlers-Danlos Syndrome, Endoplasmic Reticulum, Humans, Hydrophobic and Hydrophilic Interactions, Models, Molecular, Mutation, Peptidylprolyl Isomerase, Protein Conformation, Protein Multimerization, Protein Structure, Secondary, Protein Structure, Tertiary, Tacrolimus Binding Proteins
Show Abstract · Added November 2, 2017
The FK506-binding protein (FKBP) family consists of proteins with a variety of protein-protein interaction domains and versatile cellular functions. It is assumed that all members are peptidyl-prolyl cis-trans isomerases with the enzymatic function attributed to the FKBP domain. Six members of this family localize to the mammalian endoplasmic reticulum (ER). Four of them, FKBP22 (encoded by the FKBP14 gene), FKBP23 (FKBP7), FKBP60 (FKBP9), and FKBP65 (FKBP10), are unique among all FKBPs as they contain the EF-hand motifs. Little is known about the biological roles of these proteins, but emerging genetics studies are attracting great interest to the ER resident FKBPs, as mutations in genes encoding FKBP10 and FKBP14 were shown to cause a variety of matrix disorders. Although the structural organization of the FKBP-type domain as well as of the EF-hand motif has been known for a while, it is difficult to conclude how these structures are combined and how it affects the protein functionality. We have determined a unique 1.9 Å resolution crystal structure for human FKBP22, which can serve as a prototype for other EF hand-containing FKBPs. The EF-hand motifs of two FKBP22 molecules form a dimeric complex with an elongated and predominantly hydrophobic cavity that can potentially be occupied by an aliphatic ligand. The FKBP-type domains are separated by a cleft and their putative active sites can catalyze isomerazation of two bonds within a polypeptide chain in extended conformation. These structural results are of prime interest for understanding biological functions of ER resident FKBPs containing EF-hand motifs.
© 2013 The Protein Society.
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14 MeSH Terms
A new anti-depressive strategy for the elderly: ablation of FKBP5/FKBP51.
O'Leary JC, Dharia S, Blair LJ, Brady S, Johnson AG, Peters M, Cheung-Flynn J, Cox MB, de Erausquin G, Weeber EJ, Jinwal UK, Dickey CA
(2011) PLoS One 6: e24840
MeSH Terms: Aged, 80 and over, Animals, Blotting, Western, Corticosterone, Depressive Disorder, Humans, Immunohistochemistry, Maze Learning, Mice, Mice, Knockout, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Tacrolimus Binding Proteins
Show Abstract · Added March 9, 2015
The gene FKBP5 codes for FKBP51, a co-chaperone protein of the Hsp90 complex that increases with age. Through its association with Hsp90, FKBP51 regulates the glucocorticoid receptor (GR). Single nucleotide polymorphisms (SNPs) in the FKBP5 gene associate with increased recurrence of depressive episodes, increased susceptibility to post-traumatic stress disorder, bipolar disorder, attempt of suicide, and major depressive disorder in HIV patients. Variation in one of these SNPs correlates with increased levels of FKBP51. FKBP51 is also increased in HIV patients. Moreover, increases in FKBP51 in the amygdala produce an anxiety phenotype in mice. Therefore, we tested the behavioral consequences of FKBP5 deletion in aged mice. Similar to that of naïve animals treated with classical antidepressants FKBP5-/- mice showed antidepressant behavior without affecting cognition and other basic motor functions. Reduced corticosterone levels following stress accompanied these observed effects on depression. Age-dependent anxiety was also modulated by FKBP5 deletion. Therefore, drug discovery efforts focused on depleting FKBP51 levels may yield novel antidepressant therapies.
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13 MeSH Terms
FK506 binding protein 5 shapes stress responsiveness: modulation of neuroendocrine reactivity and coping behavior.
Touma C, Gassen NC, Herrmann L, Cheung-Flynn J, Büll DR, Ionescu IA, Heinzmann JM, Knapman A, Siebertz A, Depping AM, Hartmann J, Hausch F, Schmidt MV, Holsboer F, Ising M, Cox MB, Schmidt U, Rein T
(2011) Biol Psychiatry 70: 928-36
MeSH Terms: Adaptation, Psychological, Adult, Animals, Cells, Cultured, Corticotropin-Releasing Hormone, Dexamethasone, Dose-Response Relationship, Drug, Embryo, Mammalian, Emotions, Female, Gene Expression Regulation, Glucocorticoids, Humans, Hypothalamo-Hypophyseal System, Male, Mice, Mice, Knockout, Motor Activity, Pituitary-Adrenal System, Protein Binding, Statistics, Nonparametric, Stress, Psychological, Tacrolimus Binding Proteins, Time Factors, Young Adult
Show Abstract · Added March 9, 2015
BACKGROUND - The Hsp90 cochaperone FK506 binding protein 5 (FKBP5) is an established regulator of the glucocorticoid receptor (GR), and numerous genetic studies have linked it to stress-related diseases such as major depression or posttraumatic stress disorder. However, translational studies including genetic animal models are lacking.
METHODS - Mice deficient of FKBP5 were generated and analyzed in comparison with wildtype littermates. They were subjected to several test paradigms characterizing their emotionality, stress reactivity, and coping behavior as well as hypothalamus-pituitary-adrenal axis function and regulation. Moreover, protein expression of GR and FKBP5 was determined in different brain structures 8 days after stress exposure. The combined dexamethasone/corticotropin-releasing hormone test was performed both in mice and healthy human subjects of different FKBP5 genotypes. The GR function was evaluated by reporter gene assays.
RESULTS - Under basal conditions, deletion of FKBP5 did not change exploratory drive, locomotor activity, anxiety-related behavior, stress-coping, or depression-like behavior. After exposure to different acute stressors of sufficient intensity, however, it led to a more active coping behavior. Moreover, loss of FKBP5 decreased hypothalamus-pituitary-adrenal axis reactivity and GR expression changes in response to stressors. In mice and humans, the FKBP5 genotype also determined the outcome of the dexamethasone/corticotropin-releasing hormone test.
CONCLUSIONS - This study in mice and humans presents FKBP5 as a decisive factor for the physiological stress response, shaping neuroendocrine reactivity as well as coping behavior. 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.
Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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25 MeSH Terms
The involvement of FK506-binding protein 51 (FKBP5) in the behavioral and neuroendocrine effects of chronic social defeat stress.
Hartmann J, Wagner KV, Liebl C, Scharf SH, Wang XD, Wolf M, Hausch F, Rein T, Schmidt U, Touma C, Cheung-Flynn J, Cox MB, Smith DF, Holsboer F, Müller MB, Schmidt MV
(2012) Neuropharmacology 62: 332-9
MeSH Terms: Analysis of Variance, Animals, Corticosterone, Disease Models, Animal, Exploratory Behavior, Gene Expression Regulation, HSP90 Heat-Shock Proteins, Locomotion, Male, Maze Learning, Mice, Mice, Knockout, Neurosecretory Systems, Receptors, Glucocorticoid, Receptors, Mineralocorticoid, Stress, Psychological, Swimming, Tacrolimus Binding Proteins
Show Abstract · Added March 9, 2015
Chronic stress is increasingly considered to be a main risk factor for the development of a variety of psychiatric diseases such as depression. This is further supported by an impaired negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, which has been observed in the majority of depressed patients. The effects of glucocorticoids, the main hormonal endpoint of the HPA axis, are mediated via the glucocorticoid receptor (GR) and the mineralocorticoid receptor. The FK506-binding protein 51 (FKBP5), a co-chaperone of the Hsp90 and component of the chaperone-receptor heterocomplex, has been shown to reduce ligand sensitivity of the GR. This study aimed to investigate the function of FKBP5 as a possible mediator of the stress response system and its potential role in the development of stress-related diseases. Therefore, we assessed whether mice lacking the gene encoding FKBP5 (51KO mice) were less vulnerable to the adverse effects of three weeks of chronic social defeat stress. Mice were subsequently analyzed with regards to physiological, neuroendocrine, behavioral and mRNA expression alterations. Our results show a less vulnerable phenotype of 51KO mice with respect to physiological and neuroendocrine parameters compared to wild-type animals. 51KO mice demonstrated lower adrenal weights and basal corticosterone levels, a diminished response to a novel acute stimulus and an enhanced recovery, as well as more active stress-coping behavior. 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'.
Copyright © 2011 Elsevier Ltd. All rights reserved.
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18 MeSH Terms
Kinetics of FKBP12.6 binding to ryanodine receptors in permeabilized cardiac myocytes and effects on Ca sparks.
Guo T, Cornea RL, Huke S, Camors E, Yang Y, Picht E, Fruen BR, Bers DM
(2010) Circ Res 106: 1743-52
MeSH Terms: Animals, Blotting, Western, Calcium Signaling, Cell Membrane Permeability, Circular Dichroism, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Fluorescence Recovery After Photobleaching, Heart Ventricles, Humans, Kinetics, Mice, Mice, Knockout, Microscopy, Confocal, Mutagenesis, Site-Directed, Mutation, Myocytes, Cardiac, Phosphorylation, Protein Binding, Rats, Ryanodine Receptor Calcium Release Channel, Sarcoplasmic Reticulum, Sirolimus, Swine, Tacrolimus Binding Protein 1A, Tacrolimus Binding Proteins
Show Abstract · Added May 27, 2014
RATIONALE - FK506-binding proteins FKBP12.6 and FKBP12 are associated with cardiac ryanodine receptors (RyR2), and cAMP-dependent protein kinase A (PKA)-dependent phosphorylation of RyR2 was proposed to interrupt FKBP12.6-RyR2 association and activate RyR2. However, the function of FKBP12.6/12 and role of PKA phosphorylation in cardiac myocytes are controversial.
OBJECTIVE - To directly measure in situ binding of FKBP12.6/12 to RyR2 in ventricular myocytes, with simultaneous Ca sparks measurements as a RyR2 functional index.
METHODS AND RESULTS - We used permeabilized rat and mouse ventricular myocytes, and fluorescently-labeled FKBP12.6/12. Both FKBP12.6 and FKBP12 concentrate at Z-lines, consistent with RyR2 and Ca spark initiation sites. However, only FKBP12.6 inhibits resting RyR2 activity. Assessment of fluorescent FKBP binding in myocyte revealed a high FKBP12.6-RyR2 affinity (K(d)=0.7+/-0.1 nmol/L) and much lower FKBP12-RyR2 affinity (K(d)=206+/-70 nmol/L). Fluorescence recovery after photobleach confirmed this K(d) difference and showed that it is mediated by k(off). RyR2 phosphorylation by PKA did not alter binding kinetics or affinity of FKBP12.6/12 for RyR2. Using quantitative immunoblots, we determined endogenous [FKBP12] in intact myocytes is approximately 1 micromol/L (similar to [RyR]), whereas [FKBP12.6] is CONCLUSIONS - Only 10% to 20% of endogenous myocyte RyR2s have FKBP12.6 associated, but virtually all myocyte FKBP12.6 is RyR2-bound (because of very high affinity). FKBP12.6 but not FKBP12 inhibits basal RyR2 activity. PKA-dependent RyR2 phosphorylation has no significant effect on binding of either FKBP12 or 12.6 to RyR2 in myocytes.
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26 MeSH Terms
Cochaperone immunophilin FKBP52 is critical to uterine receptivity for embryo implantation.
Tranguch S, Cheung-Flynn J, Daikoku T, Prapapanich V, Cox MB, Xie H, Wang H, Das SK, Smith DF, Dey SK
(2005) Proc Natl Acad Sci U S A 102: 14326-31
MeSH Terms: Animals, Blotting, Northern, Blotting, Southern, Down-Regulation, Embryo Implantation, Female, Histological Techniques, In Situ Hybridization, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Chaperones, Progesterone, Receptors, Progesterone, Reverse Transcriptase Polymerase Chain Reaction, Tacrolimus Binding Proteins, Uterus
Show Abstract · Added March 9, 2015
Embryo implantation in the uterus is a critical step in mammalian reproduction, requiring preparation of the uterus receptive to blastocyst implantation. Uterine receptivity, also known as the window of implantation, lasts for a limited period, and it is during this period blastocysts normally implant. Ovarian steroid hormones estrogen and progesterone (P(4)) are the primary regulators of this process. The immunophilin FKBP52 serves as a cochaperone for steroid hormone nuclear receptors to govern appropriate hormone action in target tissues. Here we show a critical role for FKBP52 in mouse implantation. This immunophilin has unique spatiotemporal expression in the uterus during implantation, and females missing the Fkbp52 gene have complete implantation failure due to lack of attainment of uterine receptivity. The overlapping uterine expression of FKBP52 with nuclear progesterone receptor (PR) in wild-type mice together with reduced P(4) binding to PR, attenuated PR transcriptional activity and down-regulation of several P(4)-regulated genes in uteri of Fkbp52(-/-) mice, establishes this cochaperone as a critical regulator of uterine P(4) function. Interestingly, ovulation, another P(4)-mediated event, remains normal. Collectively, the present investigation provides evidence for an in vivo role for this cochaperone in regulating tissue-specific hormone action and its critical role in uterine receptivity for implantation.
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17 MeSH Terms
Physiological role for the cochaperone FKBP52 in androgen receptor signaling.
Cheung-Flynn J, Prapapanich V, Cox MB, Riggs DL, Suarez-Quian C, Smith DF
(2005) Mol Endocrinol 19: 1654-66
MeSH Terms: Animals, Blotting, Western, Dose-Response Relationship, Drug, Gene Deletion, Genetic Vectors, Genotype, HSP90 Heat-Shock Proteins, Humans, Immunohistochemistry, Male, Mice, Mice, Knockout, Models, Genetic, Models, Molecular, Molecular Chaperones, Plasmids, Point Mutation, Proline, Prostate, Protein Binding, Protein Conformation, Protein Folding, Protein Structure, Tertiary, Receptors, Androgen, Signal Transduction, Tacrolimus Binding Proteins, Testis, Tissue Distribution, Transcriptional Activation
Show Abstract · Added March 9, 2015
Molecular chaperones mediate multiple aspects of steroid receptor function, but the physiological importance of most receptor-associated cochaperones has not been determined. To help fill this gap, we targeted for disruption the mouse gene for the 52-kDa FK506 binding protein, FKBP52, a 90-kDa heat shock protein (Hsp90)-binding immunophilin found in steroid receptor complexes. A mouse line lacking FKBP52 (52KO) was generated and characterized. Male 52KO mice have several defects in reproductive tissues consistent with androgen insensitivity; among these defects are ambiguous external genitalia and dysgenic prostate. FKBP52 and androgen receptor (AR) are coexpressed in prostate epithelial cells of wild-type mice. However, FKBP52 and AR are similarly coexpressed in testis even though testis morphology and spermatogenesis in 52KO males are usually normal. Molecular studies confirm that FKBP52 is a component of AR complexes, and cellular studies in yeast and human cell models demonstrate that FKBP52 can enhance AR-mediated transactivation. AR enhancement requires FKBP52 peptidylprolyl isomerase activity as well as Hsp90-binding ability, and enhancement probably relates to an affect of FKBP52 on AR-folding pathways. In the presence of FKBP52, but not other cochaperones, the function of a minimally active AR point mutant can be dramatically restored. We conclude that FKBP52 is an AR folding factor that has critically important physiological roles in some male reproductive tissues.
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29 MeSH Terms
The FK506-binding immunophilin FKBP51 is transcriptionally regulated by progestin and attenuates progestin responsiveness.
Hubler TR, Denny WB, Valentine DL, Cheung-Flynn J, Smith DF, Scammell JG
(2003) Endocrinology 144: 2380-7
MeSH Terms: Animals, Base Sequence, Breast Neoplasms, Carcinoma, Hepatocellular, Gene Expression, Humans, Liver Neoplasms, Molecular Sequence Data, Progesterone Congeners, Promegestone, Promoter Regions, Genetic, Saimiri, Sequence Homology, Nucleic Acid, Tacrolimus, Tacrolimus Binding Proteins, Transcription, Genetic, Tumor Cells, Cultured
Show Abstract · Added March 9, 2015
FKBP51 and FKBP52 are large molecular weight FK506-binding immunophilins that have diverse biochemical functions. Best studied is the role that they play as components of steroid hormone receptors. Differential display and gene array screens have identified FKBP51 as a progestin-inducible gene. Here we demonstrate progestin enhancement of FKBP51 mRNA and protein in T-47D cells. FKBP51 mRNA and protein levels were increased 3-fold by 20 nM R5020. Induction of FKBP51 mRNA was unaffected by 1 micro g/ml cycloheximide but was blocked by the progestin receptor (PR) antagonist RU486 (1 micro M). Reporter plasmids containing 3.4 kb and 427 bp of 5'-flanking sequences of the human FKBP51 protein gene (FKBP5) exhibited regulation by progestin in T-47D cells. A construct containing 19 bp of upstream sequence demonstrated diminished basal activity and no stimulation by R5020. To test whether elevated FKBP51 affects progestin responsiveness, HepG2 cells were transfected with human FKBP51, PR, and mouse mammary tumor virus-luciferase plasmids, and treated with R5020 (0.03-10 nM). Expression of FKBP51 increased the EC(50) for PR transactivation by 3.2-fold. Expression of FKBP51 from squirrel monkey, a New World primate with naturally occurring progestin resistance, increased the EC(50) more dramatically (11.7-fold vs. control). Expression of FKBP51 bearing a double-point mutation in the tetratricopeptide repeat domain had no effect on PR transactivation. These results suggest that increased expression of FKBP51 by progestin may attenuate progestin responsiveness in hormone-conditioned cells. Furthermore, overexpression of FKBP51 in the squirrel monkey may be a contributing cause of progesterone resistance in this species.
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17 MeSH Terms