Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The breast cancer susceptibility gene (BRCA2) is localized mainly in the nucleus where it plays an important role in DNA damage repair. Some BRCA2 protein is also present in the centrosome. Here, we demonstrate that BRCA2 interacts with plectin, a cytoskeletal cross-linker protein, and that this interaction controls the position of the centrosome. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin B (CDK1/CycB) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of HeLa cells by adding activated CDK1/CycB kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane. Plectin has six homologous ankyrin-like repeat domains (termed PLEC M1-M6). Using a pull-down assay, we found that GST-PLEC M1 and a GST-C-terminal region fusion protein (which comprised PLEC M6, along with an adjacent vimentin site) interacted with BRCA2. Since each PLEC module exhibits high homology to the others, the possibility of all six domains participating in this interaction was indicated. Moreover, when PLEC M1 was overexpressed in HeLa cells, it competed with endogenous plectin and inhibited the BRCA2-plectin interaction. This inhibitory effect resulted in dissociation of the centrosomes from the nucleus and increased the rate of micronuclei formation which may lead to carcinogenesis. In addition, when either BRCA2 or plectin was suppressed by the appropriate siRNA, a similar change in centrosomal positioning was observed. We suggest that the BRCA2-plectin interaction plays an important role in the regulation of centrosome localization and also that displacement of the centrosome may result in genomic instability and cancer development.
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PMID:BRCA2 interacts with the cytoskeletal linker protein plectin to form a complex controlling centrosome localization. 1970 76

The Rab family belongs to the Ras-like small GTPase superfamily and is implicated in membrane trafficking through interaction with specific effector molecules. Because of the large number of Rab isoforms in mammals, however, the effectors of most of the mammalian Rabs are yet to be identified. In this study, we systematically screened five different cell or tissue lysates for novel Rab effectors by a combination of glutathione S-transferase (GST) pull-down assay with 60 different mammalian Rabs and mass spectroscopic analysis. Three of the 21 Rab-binding proteins we identified, mKIAA1055/TBC1D2B (Rab22-binding protein), GAPCenA/TBC1D11 (Rab36-binding protein) and centaurin beta2/ACAP2 (Rab35-binding protein), are GTPase-activating proteins (GAPs) for Rab or Arf. Although it has recently been proposed that the Rab-GAP (Tre-2 /Bub2/Cdc16) domain physically interacts with its substrate Rab, these three GAPs interacted with specific Rabs via a domain other than a GAP domain, e.g. centaurin beta2 binds GTP-Rab35 via the ankyrin repeat (ANKR) domain. Although centaurin beta2 did not exhibit any Rab35-GAP activity in vitro, the Rab35-binding ANKR domain of centaurin beta2 was found to be required for its plasma membrane localization and regulation of Rab35-dependent neurite outgrowth of PC12 cells through inactivation of Arf6. These findings suggest a novel mode of interaction between Rab and GAP.
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PMID:Comprehensive screening for novel rab-binding proteins by GST pull-down assay using 60 different mammalian Rabs. 2007 Jun 12

Up to 5% of untreated female Onchocerca volvulus filariae develop potentially fatal pleomorphic neoplasms, whose incidence is increased following ivermectin treatment. We studied the occurrence of 8 filarial proteins and of Wolbachia endobacteria in the tumor cells. Onchocercomas from patients, untreated and treated with antibiotics and anthelminthics, were examined by immunohistology. Neoplasms were diagnosed in 112 of 3587 female and in 2 of 1570 male O. volvulus. The following proteins and other compounds of O. volvulus were expressed in the cells of the neoplasms: glutathione S-transferase 1, lysosomal aspartic protease, cAMP-dependent protein kinase, alpha-enolase, aspartate aminotransferase, ankyrin E1, tropomyosin, heat shock protein 60, transforming growth factor-beta, and prostaglandin E(2). These findings prove the filarial origin of the neoplasms and confirm the pleomorphism of the tumor cells. Signs indicating malignancy of the neoplasms are described. Wolbachia were observed in the hypodermis, oocytes, and embryos of tumor-harbouring filariae using antibodies against Wolbachia surface protein, Wolbachia HtrA-type serine protease, and Wolbachia aspartate aminotransferase. In contrast, Wolbachia were not found in the cells of the neoplasms. Further, neoplasm-containing worms were not observed after more than 10 months after the start of sufficient treatment with doxycycline or doxycycline plus ivermectin.
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PMID:Immunohistological studies on neoplasms of female and male Onchocerca volvulus: filarial origin and absence of Wolbachia from tumor cells. 2019 97

TRPN1 is a candidate mechanotransduction channel in Drosophila and Caenorhabditis elegans, also present in hair cells of lower vertebrates. At its N-terminal cytoplasmic tail it contains 28 ankyrin repeats. We performed a yeast two-hybrid screen with the N-terminal ankyrin repeats of Xenopus TRPN1 as bait and identified the Penta-EF-hand protein peflin as a putative interaction partner. We confirmed this interaction by GST pulldown assays and by co-localization in an epithelial cell model. Collectively, our study identifies peflin as an interaction partner of TRPN1 in vitro.
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PMID:Transient receptor potential N (TRPN1) from Xenopus interacts with the penta-EF-hand protein peflin. 2315 37

The main tasks of skeletal muscle are muscle contraction and relaxation, which are mediated by changes in cytosolic Ca(2+) levels. Canonical-type transient receptor potential 3 (TRPC3) contains an ankyrin repeat (AR) region at the N-terminus (38-188 amino acids) and forms extracellular Ca(2+)-entry channels by homo or heteromerization with other TRP subtypes in various cells including skeletal myotubes. However, previous research has not determined which region(s) of TRPC3 is responsible for the heteromerization, whether the AR region participates in the heteromerizations, or what is the role of heteromeric TRPC3s in skeletal muscle. In the present study, the heteromerization of TRPC3 with TRPC1 was first examined by GST pull-down assays of TRPC3 portions with TRPC1. The portion containing the AR region of TRPC3 was bound to the TRPC1, but the binding was inhibited by the very end sub-region of the TRPC3 (1-37 amino acids). In-silico studies have suggested that the very end sub-region possibly induces a structural change in the AR region. Second, the very end sub-region of TRPC3 was expressed in mouse primary skeletal myotubes, resulting in a dominant-negative inhibition of heteromeric TRPC3/1 formation. In addition, the skeletal myotubes expressing the very end sub-region showed a decrease in resting cytosolic Ca(2+) levels. These results suggest that the AR region of TRPC3 could mediate the heteromeric TRPC3/1 formation, and the heteromeric TRPC3/1 could participate in regulating the resting cytosolic Ca(2+) levels in skeletal muscle.
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PMID:Heteromeric TRPC3 with TRPC1 formed via its ankyrin repeats regulates the resting cytosolic Ca2+ levels in skeletal muscle. 2461 81

The tetrodotoxin-resistant (TTX-R) voltage-gated sodium channel Nav 1.8 is predominantly expressed in peripheral afferent neurons, but in case of neuronal injury an ectopic and detrimental expression of Nav 1.8 occurs in neurons of the CNS. In CNS neurons, Nav 1.2 and Nav 1.6 channels accumulate at the axon initial segment, the site of the generation of the action potential, through a direct interaction with the scaffolding protein ankyrin G (ankG). This interaction is regulated by protein kinase CK2 phosphorylation. In this study, we quantitatively analyzed the interaction between Nav 1.8 and ankG. GST pull-down assay and surface plasmon resonance technology revealed that Nav 1.8 strongly and constitutively interacts with ankG, in comparison to what observed for Nav 1.2. An ion channel bearing the ankyrin-binding motif of Nav 1.8 displaced the endogenous Nav 1 accumulation at the axon initial segment of hippocampal neurons. Finally, Nav 1.8 and ankG co-localized in skin nerves fibers. Altogether, these results indicate that Nav 1.8 carries all the information required for its localization at ankG micro-domains. The constitutive binding of Nav 1.8 with ankG could contribute to the pathological aspects of illnesses where Nav 1.8 is ectopically expressed in CNS neurons.
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PMID:Tetrodotoxin-resistant voltage-gated sodium channel Nav 1.8 constitutively interacts with ankyrin G. 2490 31

Ethylene is a gaseous hormone that regulates many processes involved in plant growth, development and stress responses. Previously, we found that the tobacco ethylene receptor NTHK1 (Nicotiana tabacum histidine kinase 1) promotes seedling growth and affects plant salt stress responses. In this study, NTHK1 ethylene receptor-interacting protein 2 (NEIP2) was identified and further characterized in relation to these processes. NEIP2 contains three ankyrin repeats that mediate an interaction with NTHK1 as demonstrated by yeast two-hybrid, glutathione S-transferase (GST) pull-down and co-immunoprecipitation assays. NTHK1 phosphorylates NEIP2 in vitro. Salt stress and ethylene treatment induce NEIP2 accumulation in the first few hours and then the NEIP2 can be phosphorylated in planta. The overexpression of NTHK1 enhances NEIP2 accumulation in the presence of ethylene and salt stress. NEIP2 overexpression promotes plant growth but reduces ethylene responses, which is consistent with the functions of NTHK1. Additionally, NEIP2 improves plant performance under salt and oxidative stress. These results suggest that ethylene-induced NEIP2 probably acts as a brake to reduce ethylene response but resumes growth through interaction with NTHK1. Manipulation of NEIP2 may be beneficial for crop improvement.
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PMID:Tobacco ankyrin protein NEIP2 interacts with ethylene receptor NTHK1 and regulates plant growth and stress responses. 2563 61

Ring1 and YY1 Binding Protein (RYBP) induces tumor-specific cell apoptosis, but the underlying molecular mechanism has not been fully understood. Here we conducted a yeast two hybrid screen and identified FANK1 (Fibronectin type III and ankyrin repeat domains 1) as a novel RYBP-interacting protein. This interaction was confirmed by coimmunoprecipitation, GST pulldown and immunofluorescence assays. We mapped that the FNIII domain at the N-terminal of FANK1 binds to the Serine/Threonine-rich region at the C-terminal of RYBP. Further studies showed that overexpression of RYBP stabilized, whereas knockdown of RYBP by its specific shRNAs reduced, the expression of FANK1. Mechanistic studies revealed that RYBP inhibited the proteasome degradation of polyubiquitinated FANK1, thus prolonging the half-life of FANK1 protein. Functional studies indicated that RYBP activates FANK1-mediated activator protein 1 (AP-1) signaling pathway which contributes to tumor cell apoptosis. Taken together, our current study uncovered a new mechanism which RYBP utilizes to exert its pro-apoptotic activity in human tumor cells.
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PMID:Proapoptotic RYBP interacts with FANK1 and induces tumor cell apoptosis through the AP-1 signaling pathway. 2706 Apr 96

Leucine-rich repeat kinase-1 (Lrrk1) consists of ankyrin repeats (ANK), leucine-rich repeats (LRR), a GTPase-like domain of Roc (ROC), a COR domain, a serine/threonine kinase domain (KD), and WD40 repeats (WD40). Previous studies have revealed that knockout (KO) of Lrrk1 in mice causes severe osteopetrosis, and a human mutation of Lrrk1 leads to osteosclerotic metaphysial dysplasia. The molecular mechanism by which Lrrk1 regulates osteoclast function is unknown. In this study, we generated a series of Lrrk1 mutants and evaluated their ability to rescue defective bone resorption in Lrrk1-deficient osteoclasts by use of pit formation assays. Overexpression of Lrrk1 or LRR-truncated Lrrk1, but not ANK-truncated Lrrk1, WD40-truncated Lrrk1, Lrrk1-KD, or K651A mutant Lrrk1, rescued bone resorption function of Lrrk1 KO osteoclasts. We next examined whether RAC1/Cdc42 small GTPases are direct substrates of Lrrk1 in osteoclasts. Western blot and pull-down assays revealed that Lrrk1 deficiency in osteoclasts resulted in reduced phosphorylation and activation of RAC1/Cdc42. In vitro kinase assays confirmed that recombinant Lrrk1 phosphorylated RAC1-GST protein, and immunoprecipitation showed that the interaction of Lrrk1 with RAC1 occurred within 10 min after RANKL treatment. Overexpression of constitutively active Q61L RAC1 partially rescued the resorptive function of Lrrk1-deficient osteoclasts. Furthermore, lack of Lrrk1 in osteoclasts led to reduced autophosphorylation of p21 protein-activated kinase-1 at Ser¹⁴⁴, catalyzed by RAC1/Cdc42 binding and activation. Our data indicate that Lrrk1 regulates osteoclast function by directly modulating phosphorylation and activation of small GTPase RAC1/Cdc42 and that its function depends on ANK, ROC, WD40, and kinase domains.
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PMID:Leucine-rich repeat kinase-1 regulates osteoclast function by modulating RAC1/Cdc42 Small GTPase phosphorylation and activation. 2760 Aug 24


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