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Pesquisa : G02.111.660.871.790.600.400 [Categoria DeCS]
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  1 / 1848 MEDLINE  
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[PMID]:29311697
[Au] Autor:Qureshi BM; Schmidt A; Behrmann E; Bürger J; Mielke T; Spahn CMT; Heck M; Scheerer P
[Ad] Endereço:Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, D-10117, Berlin, Germany.
[Ti] Título:Mechanistic insights into the role of prenyl-binding protein PrBP/δ in membrane dissociation of phosphodiesterase 6.
[So] Source:Nat Commun;9(1):90, 2018 01 08.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Isoprenylated proteins are associated with membranes and their inter-compartmental distribution is regulated by solubilization factors, which incorporate lipid moieties in hydrophobic cavities and thereby facilitate free diffusion during trafficking. Here we report the crystal structure of a solubilization factor, the prenyl-binding protein (PrBP/δ), at 1.81 Å resolution in its ligand-free apo-form. Apo-PrBP/δ harbors a preshaped, deep hydrophobic cavity, capacitating apo-PrBP/δ to readily bind its prenylated cargo. To investigate the molecular mechanism of cargo solubilization we analyzed the PrBP/δ-induced membrane dissociation of rod photoreceptor phosphodiesterase (PDE6). The results suggest that PrBP/δ exclusively interacts with the soluble fraction of PDE6. Depletion of soluble species in turn leads to dissociation of membrane-bound PDE6, as both are in equilibrium. This "solubilization by depletion" mechanism of PrBP/δ differs from the extraction of prenylated proteins by the similar folded solubilization factor RhoGDI, which interacts with membrane bound cargo via an N-terminal structural element lacking in PrBP/δ.
[Mh] Termos MeSH primário: Proteínas de Transporte/metabolismo
Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/metabolismo
Neopreno/metabolismo
Células Fotorreceptoras Retinianas Bastonetes/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteínas de Transporte/química
Bovinos
Cristalografia por Raios X
Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/química
Modelos Moleculares
Complexos Multiproteicos/química
Complexos Multiproteicos/metabolismo
Neopreno/química
Ligação Proteica
Domínios Proteicos
Prenilação de Proteína
Subunidades Proteicas/química
Subunidades Proteicas/metabolismo
Inibidores da Dissociação do Nucleotídeo Guanina rho-Específico/química
Inibidores da Dissociação do Nucleotídeo Guanina rho-Específico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Multiprotein Complexes); 0 (Protein Subunits); 0 (prenyl); 0 (rho-Specific Guanine Nucleotide Dissociation Inhibitors); 9010-98-4 (Neoprene); EC 3.1.4.35 (Cyclic Nucleotide Phosphodiesterases, Type 6)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180110
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02569-y


  2 / 1848 MEDLINE  
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[PMID]:29180010
[Au] Autor:Maeda A; Uchida M; Nishikawa S; Nishino T; Konishi H
[Ad] Endereço:Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shobara, Hiroshima 727-0023, Japan.
[Ti] Título:Role of N-myristoylation in stability and subcellular localization of the CLPABP protein.
[So] Source:Biochem Biophys Res Commun;495(1):1249-1256, 2018 01 01.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cardiolipin and phosphatidic acid-binding protein (CLPABP) controls the stability of the mRNA harboring an AU-rich element (ARE) in the 3' UTR with the help of the RNA stabilizer, human antigen R (HuR). Although CLPABP is localized on the mitochondrial surface as a large protein-RNA complex, its precise role is not yet known. Recently, CLPABP was identified as an N-myristoylated protein. Here, we demonstrate the effects of N-myristoylation on the functions of CLPABP. In the present study, compared to the wild-type protein that possessed the "MG" motif at the N-terminus for N-myristoylation, the mutant CLPABP protein that lacked N-myristoylation modification site was unstable. Furthermore, the expression of the G/A mutant of CLPABP, which lacked N-myristoylation site, induced morphological alterations in mitochondria. Because pleckstrin homology domain-deleted mutant, which was fused with the N-myristoylation site derived from intact CLPABP, could not colocalize with mitochondria, N-myristoylation of CLPABP was predicted to affect its stability onto the mitochondrial membrane rather than its subcellular localization.
[Mh] Termos MeSH primário: Metabolismo dos Lipídeos/fisiologia
Proteínas Ligadas a Lipídeos/metabolismo
Ácido Mirístico/metabolismo
Prenilação de Proteína/fisiologia
Frações Subcelulares/metabolismo
[Mh] Termos MeSH secundário: Animais
Células COS
Cercopithecus aethiops
Células HEK293
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Lipid-Linked Proteins); 0 (PLEKHN1 protein, human); 0I3V7S25AW (Myristic Acid)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180105
[Lr] Data última revisão:
180105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171129
[St] Status:MEDLINE


  3 / 1848 MEDLINE  
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[PMID]:28630045
[Au] Autor:Shimizu H; Toma-Fukai S; Saijo S; Shimizu N; Kontani K; Katada T; Shimizu T
[Ad] Endereço:From the Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
[Ti] Título:Structure-based analysis of the guanine nucleotide exchange factor SmgGDS reveals armadillo-repeat motifs and key regions for activity and GTPase binding.
[So] Source:J Biol Chem;292(32):13441-13448, 2017 Aug 11.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Small GTPases are molecular switches that have critical biological roles and are controlled by GTPase-activating proteins and guanine nucleotide exchange factors (GEFs). The smg GDP dissociation stimulator (SmgGDS) protein functions as a GEF for the RhoA and RhoC small GTPases. SmgGDS has various regulatory roles, including small GTPase trafficking and localization and as a molecular chaperone, and interacts with many small GTPases possessing polybasic regions. Two SmgGDS splice variants, SmgGDS-558 and SmgGDS-607, differ in GEF activity and binding affinity for RhoA depending on the lipidation state, but the reasons for these differences are unclear. Here we determined the crystal structure of SmgGDS-558, revealing a fold containing tandem copies of armadillo repeats not present in other GEFs. We also observed that SmgGDS harbors distinct positively and negatively charged regions, both of which play critical roles in binding to RhoA and GEF activity. This is the first report demonstrating a relationship between the molecular function and atomic structure of SmgGDS. Our findings indicate that the two SmgGDS isoforms differ in GTPase binding and GEF activity, depending on the lipidation state, thus providing useful information about the cellular functions of SmgGDS in cells.
[Mh] Termos MeSH primário: Fatores de Troca do Nucleotídeo Guanina/metabolismo
Modelos Moleculares
Prenilação de Proteína
Proteína rhoA de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Motivos de Aminoácidos
Substituição de Aminoácidos
Sítios de Ligação
Farnesiltranstransferase/genética
Farnesiltranstransferase/metabolismo
Fatores de Troca do Nucleotídeo Guanina/química
Fatores de Troca do Nucleotídeo Guanina/genética
Seres Humanos
Cinética
Simulação de Acoplamento Molecular
Mutagênese Sítio-Dirigida
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Mutação Puntual
Isoformas de Proteínas/química
Isoformas de Proteínas/genética
Isoformas de Proteínas/metabolismo
Multimerização Proteica
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Sequências Repetitivas de Aminoácidos
Solubilidade
Ressonância de Plasmônio de Superfície
Proteína rhoA de Ligação ao GTP/química
Proteína rhoA de Ligação ao GTP/genética
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Guanine Nucleotide Exchange Factors); 0 (Peptide Fragments); 0 (Protein Isoforms); 0 (RAP1GDS1 protein, human); 0 (Recombinant Fusion Proteins); 0 (Recombinant Proteins); 124671-05-2 (RHOA protein, human); EC 2.5.1.29 (Farnesyltranstransferase); EC 3.6.5.2 (rhoA GTP-Binding Protein)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170825
[Lr] Data última revisão:
170825
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170621
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.792556


  4 / 1848 MEDLINE  
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[PMID]:28546426
[Au] Autor:Emery AC; Xu W; Eiden MV; Eiden LE
[Ad] Endereço:From the Section on Molecular Neuroscience and.
[Ti] Título:Guanine nucleotide exchange factor Epac2-dependent activation of the GTP-binding protein Rap2A mediates cAMP-dependent growth arrest in neuroendocrine cells.
[So] Source:J Biol Chem;292(29):12220-12231, 2017 Jul 21.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:First messenger-dependent activation of MAP kinases in neuronal and endocrine cells is critical for cell differentiation and function and requires guanine nucleotide exchange factor (GEF)-mediated activation of downstream Ras family small GTPases, which ultimately lead to ERK, JNK, and p38 phosphorylation. Because there are numerous GEFs and also a host of Ras family small GTPases, it is important to know which specific GEF-small GTPase dyad functions in a given cellular process. Here we investigated the upstream activators and downstream effectors of signaling via the GEF Epac2 in the neuroendocrine NS-1 cell line. Three cAMP sensors, Epac2, PKA, and neuritogenic cAMP sensor-Rapgef2, mediate distinct cellular outputs: p38-dependent growth arrest, cAMP response element-binding protein-dependent cell survival, and ERK-dependent neuritogenesis, respectively, in these cells. Previously, we found that cAMP-induced growth arrest of PC12 and NS-1 cells requires Epac2-dependent activation of p38 MAP kinase, which posed the important question of how Epac2 engages p38 without simultaneously activating other MAP kinases in neuronal and endocrine cells. We now show that the small GTP-binding protein Rap2A is the obligate effector for, and GEF substrate of, Epac2 in mediating growth arrest through p38 activation in NS-1 cells. This new pathway is distinctly parcellated from the G protein-coupled receptor → G → adenylate cyclase → cAMP → PKA → cAMP response element-binding protein pathway mediating cell survival and the G protein-coupled receptor → G → adenylate cyclase → cAMP → neuritogenic cAMP sensor-Rapgef2 → B-Raf → MEK → ERK pathway mediating neuritogenesis in NS-1 cells.
[Mh] Termos MeSH primário: AMP Cíclico/metabolismo
Fatores de Troca do Nucleotídeo Guanina/metabolismo
Sistema de Sinalização das MAP Quinases
Células Neuroendócrinas/metabolismo
Processamento de Proteína Pós-Traducional
Proteínas rap de Ligação ao GTP/agonistas
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Ativação Enzimática
Proteínas de Ligação ao GTP/química
Proteínas de Ligação ao GTP/genética
Proteínas de Ligação ao GTP/metabolismo
Proteínas de Fluorescência Verde/genética
Proteínas de Fluorescência Verde/metabolismo
Ligantes
Proteínas Monoméricas de Ligação ao GTP/antagonistas & inibidores
Proteínas Monoméricas de Ligação ao GTP/genética
Proteínas Monoméricas de Ligação ao GTP/metabolismo
Proteínas do Tecido Nervoso/agonistas
Proteínas do Tecido Nervoso/antagonistas & inibidores
Proteínas do Tecido Nervoso/genética
Proteínas do Tecido Nervoso/metabolismo
Neuritos/metabolismo
Células Neuroendócrinas/citologia
Neurogênese
Fosforilação
Prenilação de Proteína
Interferência de RNA
Ratos
Proteínas Recombinantes/metabolismo
Proteínas rap de Ligação ao GTP/antagonistas & inibidores
Proteínas rap de Ligação ao GTP/genética
Proteínas rap de Ligação ao GTP/metabolismo
Proteínas ras/antagonistas & inibidores
Proteínas ras/genética
Proteínas ras/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Epac-2 protein, rat); 0 (Guanine Nucleotide Exchange Factors); 0 (Ligands); 0 (Nerve Tissue Proteins); 0 (Rap2a protein, rat); 0 (Recombinant Proteins); 147336-22-9 (Green Fluorescent Proteins); E0399OZS9N (Cyclic AMP); EC 3.6.1.- (GTP-Binding Proteins); EC 3.6.5.2 (Monomeric GTP-Binding Proteins); EC 3.6.5.2 (Rit1 protein, rat); EC 3.6.5.2 (rap GTP-Binding Proteins); EC 3.6.5.2 (ras Proteins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170808
[Lr] Data última revisão:
170808
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170527
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.790329


  5 / 1848 MEDLINE  
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[PMID]:28531892
[Au] Autor:Angori S; Capanni C; Faulkner G; Bean C; Boriani G; Lattanzi G; Cenni V
[Ad] Endereço:Institute of Molecular Genetics (IGM)-CNR, Unit of Bologna, Bologna, Italy.
[Ti] Título:Emery-Dreifuss Muscular Dystrophy-Associated Mutant Forms of Lamin A Recruit the Stress Responsive Protein Ankrd2 into the Nucleus, Affecting the Cellular Response to Oxidative Stress.
[So] Source:Cell Physiol Biochem;42(1):169-184, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Ankrd2 is a stress responsive protein mainly expressed in muscle cells. Upon the application of oxidative stress, Ankrd2 translocates into the nucleus where it regulates the activity of genes involved in cellular response to stress. Emery-Dreifuss Muscular Dystrophy 2 (EDMD2) is a muscular disorder caused by mutations of the gene encoding lamin A, LMNA. As well as many phenotypic abnormalities, EDMD2 muscle cells also feature a permanent basal stress state, the underlying molecular mechanisms of which are currently unclear. METHODS: Experiments were performed in EDMD2-lamin A overexpressing cell lines and EDMD2-affected human myotubes. Oxidative stress was produced by H2O2 treatment. Co-immunoprecipitation, cellular subfractionation and immunofluorescence analysis were used to validate the relation between Ankrd2 and forms of lamin A; cellular sensibility to stress was monitored by the analysis of Reactive Oxygen Species (ROS) release and cell viability. RESULTS: Our data demonstrate that oxidative stress induces the formation of a complex between Ankrd2 and lamin A. However, EDMD2-lamin A mutants were able to bind and mislocalize Ankrd2 in the nucleus even under basal conditions. Nonetheless, cells co-expressing Ankrd2 and EDMD2-lamin A mutants were more sensitive to oxidative stress than the Ankrd2-wild type lamin A counterpart. CONCLUSIONS: For the first time, we present evidence that in muscle fibers from patients affected by EDMD2, Ankrd2 has an unusual nuclear localization. By introducing a plausible mechanism ruling this accumulation, our data hint at a novel function of Ankrd2 in the pathogenesis of EDMD2-affected cells.
[Mh] Termos MeSH primário: Núcleo Celular/metabolismo
Lamina Tipo A/metabolismo
Proteínas Musculares/metabolismo
Distrofia Muscular de Emery-Dreifuss/patologia
Proteínas Nucleares/metabolismo
Estresse Oxidativo
Proteínas Repressoras/metabolismo
[Mh] Termos MeSH secundário: Sobrevivência Celular/efeitos dos fármacos
Células Cultivadas
Células HEK293
Seres Humanos
Peróxido de Hidrogênio/toxicidade
Imunoprecipitação
Lamina Tipo A/química
Lamina Tipo A/genética
Microscopia de Fluorescência
Proteínas Musculares/química
Proteínas Musculares/genética
Músculo Esquelético/citologia
Músculo Esquelético/efeitos dos fármacos
Músculo Esquelético/metabolismo
Distrofia Muscular de Emery-Dreifuss/genética
Distrofia Muscular de Emery-Dreifuss/metabolismo
Mioblastos/citologia
Mioblastos/efeitos dos fármacos
Mioblastos/metabolismo
Proteínas Nucleares/química
Proteínas Nucleares/genética
Estresse Oxidativo/efeitos dos fármacos
Plasmídeos/genética
Plasmídeos/metabolismo
Ligação Proteica
Prenilação de Proteína/efeitos dos fármacos
Espécies Reativas de Oxigênio/metabolismo
Proteínas Repressoras/química
Proteínas Repressoras/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ANKRD2 protein, human); 0 (Lamin Type A); 0 (Muscle Proteins); 0 (Nuclear Proteins); 0 (Reactive Oxygen Species); 0 (Repressor Proteins); 0 (prelamin A); BBX060AN9V (Hydrogen Peroxide)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170523
[St] Status:MEDLINE
[do] DOI:10.1159/000477309


  6 / 1848 MEDLINE  
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[PMID]:28521678
[Au] Autor:Liu LM; Xu Y; Chou KC
[Ad] Endereço:School of Statistics, Capital University of Economics and Business, Beijing 100070, China.
[Ti] Título:iPGK-PseAAC: Identify Lysine Phosphoglycerylation Sites in Proteins by Incorporating Four Different Tiers of Amino Acid Pairwise Coupling Information into the General PseAAC.
[So] Source:Med Chem;13(6):552-559, 2017.
[Is] ISSN:1875-6638
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Occurring at Lys residues, the PGK (lysine phosphoglycerylation) is a special kind of post-translational modification (PTM). It may invert the charge potential of the modified residue and change the protein structures and functions, causing various diseases in liver, brain, and kidney. OBJECTIVE: From the angles of both basic research and drug development, we are facing a critical challenging problem: for an uncharacterized protein sequence containing many Lys residues, which ones can be of phosphoglycerylation, and which ones cannot? METHOD: To address this problem, we have developed a predictor called iPGK-PseAAC by incorporating into the general PseAAC (pseudo amino acid composition) with four different tiers of amino acid pairwise coupling information, where tiers 1, 2, 3, and 4 refer to the amino acid pairwise couplings between all the 1st, 2nd, 3rd, and 4th most contiguous residues along a protein segment, respectively. RESULTS: Rigorous cross-validations indicated that the proposed predictor remarkably outperformed its existing counterparts. CONCLUSION: The proposed predictor iPGK-PseAAC will become a very useful bioinformatics tool for medicinal chemistry. For the convenience of most experimental scientists, a user-friendly webserver for iGPK-PseAAC has been established at http://app.aporc.org/iPGK-PseAAC/, by which users can easily obtain their desired results without the need to go through the complicated mathematical equations involved.
[Mh] Termos MeSH primário: Biologia Computacional/métodos
Cisteína/metabolismo
Prenilação de Proteína
[Mh] Termos MeSH secundário: Algoritmos
Sequência de Aminoácidos
Benchmarking
Sítios de Ligação
Reprodutibilidade dos Testes
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
K848JZ4886 (Cysteine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170520
[St] Status:MEDLINE
[do] DOI:10.2174/1573406413666170515120507


  7 / 1848 MEDLINE  
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[PMID]:28425870
[Au] Autor:Xu Y; Wang Z; Li C; Chou KC
[Ad] Endereço:Department of Information and Computer Science, University of Science and Technology Beijing, Beijing 100083, China.
[Ti] Título:iPreny-PseAAC: Identify C-terminal Cysteine Prenylation Sites in Proteins by Incorporating Two Tiers of Sequence Couplings into PseAAC.
[So] Source:Med Chem;13(6):544-551, 2017.
[Is] ISSN:1875-6638
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Occurring at the cysteine residue in the C-terminal of a protein, prenylation is a special kind of post-translational modification (PTM), which may play a key role for statin in altering immune function. Therefore, knowledge of the prenylation sites in proteins is important for drug development as well as for in-depth understanding the biological process concerned. OBJECTIVE: Given a query protein whose C-terminal contains some cysteine residues, which one can be of prenylation or none of them can be prenylated? METHODS: To address this problem, we have developed a new predictor, called "iPreny-PseAAC", by incorporating two tiers of sequence pair coupling effects into the general form of PseAAC (pseudo amino acid composition). RESULTS: It has been observed by four different cross-validation approaches that all the important indexes in reflecting its prediction quality are quite high and fully consistent to each other. CONCLUSION: It is anticipated that the iPreny-PseAAC predictor holds very high potential to become a useful high throughput tool in identifying protein C-terminal cysteine prenylation sites and the other relevant areas. To maximize the convenience for most experimental biologists, the webserver for the new predictor has been established at http://app.aporc.org/iPreny-PseAAC/, by which users can easily get their desired results without needing to go through the mathematical details involved in this paper.
[Mh] Termos MeSH primário: Biologia Computacional/métodos
Cisteína/metabolismo
Prenilação de Proteína
[Mh] Termos MeSH secundário: Algoritmos
Sequência de Aminoácidos
Sítios de Ligação
Internet
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
K848JZ4886 (Cysteine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170421
[St] Status:MEDLINE
[do] DOI:10.2174/1573406413666170419150052


  8 / 1848 MEDLINE  
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[PMID]:28395021
[Au] Autor:Duluc L; Ahmetaj-Shala B; Mitchell J; Abdul-Salam VB; Mahomed AS; Aldabbous L; Oliver E; Iannone L; Dubois OD; Storck EM; Tate EW; Zhao L; Wilkins MR; Wojciak-Stothard B
[Ad] Endereço:Department of Medicine, Hammersmith Campus, Imperial College London, Du Cane Road, W120NN London, UK.
[Ti] Título:Tipifarnib prevents development of hypoxia-induced pulmonary hypertension.
[So] Source:Cardiovasc Res;113(3):276-287, 2017 Mar 01.
[Is] ISSN:1755-3245
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Aims: RhoB plays a key role in the pathogenesis of hypoxia-induced pulmonary hypertension. Farnesylated RhoB promotes growth responses in cancer cells and we investigated whether inhibition of protein farnesylation will have a protective effect. Methods and results: The analysis of lung tissues from rodent models and pulmonary hypertensive patients showed increased levels of protein farnesylation. Oral farnesyltransferase inhibitor tipifarnib prevented development of hypoxia-induced pulmonary hypertension in mice. Tipifarnib reduced hypoxia-induced vascular cell proliferation, increased endothelium-dependent vasodilatation and reduced vasoconstriction of intrapulmonary arteries without affecting cell viability. Protective effects of tipifarnib were associated with inhibition of Ras and RhoB, actin depolymerization and increased eNOS expression in vitro and in vivo. Farnesylated-only RhoB (F-RhoB) increased proliferative responses in cultured pulmonary vascular cells, mimicking the effects of hypoxia, while both geranylgeranylated-only RhoB (GG-RhoB), and tipifarnib had an inhibitory effect. Label-free proteomics linked F-RhoB with cell survival, activation of cell cycle and mitochondrial biogenesis. Hypoxia increased and tipifarnib reduced the levels of F-RhoB-regulated proteins in the lung, reinforcing the importance of RhoB as a signalling mediator. Unlike simvastatin, tipifarnib did not increase the expression levels of Rho proteins. Conclusions: Our study demonstrates the importance of protein farnesylation in pulmonary vascular remodelling and provides a rationale for selective targeting of this pathway in pulmonary hypertension.
[Mh] Termos MeSH primário: Anti-Hipertensivos/farmacologia
Inibidores Enzimáticos/farmacologia
Farnesiltranstransferase/antagonistas & inibidores
Hipertensão Pulmonar/prevenção & controle
Hipóxia/tratamento farmacológico
Artéria Pulmonar/efeitos dos fármacos
Quinolonas/farmacologia
[Mh] Termos MeSH secundário: Animais
Proliferação Celular/efeitos dos fármacos
Células Cultivadas
Modelos Animais de Doenças
Células Endoteliais/efeitos dos fármacos
Células Endoteliais/enzimologia
Células Endoteliais/patologia
Farnesiltranstransferase/metabolismo
Seres Humanos
Hipertensão Pulmonar/enzimologia
Hipertensão Pulmonar/etiologia
Hipóxia/complicações
Hipóxia/enzimologia
Masculino
Camundongos Endogâmicos C57BL
Fenótipo
Prenilação de Proteína
Proteômica/métodos
Artéria Pulmonar/enzimologia
Artéria Pulmonar/patologia
Artéria Pulmonar/fisiopatologia
Fatores de Tempo
Transfecção
Vasoconstrição/efeitos dos fármacos
Vasodilatação/efeitos dos fármacos
Proteína rhoB de Ligação ao GTP/genética
Proteína rhoB de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antihypertensive Agents); 0 (Enzyme Inhibitors); 0 (Quinolones); EC 2.5.1.29 (Farnesyltranstransferase); EC 3.6.5.2 (rhoB GTP-Binding Protein); MAT637500A (tipifarnib)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170411
[St] Status:MEDLINE
[do] DOI:10.1093/cvr/cvw258


  9 / 1848 MEDLINE  
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[PMID]:28359055
[Au] Autor:Tricarico PM; Romeo A; Gratton R; Crovella S; Celsi F
[Ad] Endereço:Institute for Maternal and Child Health - IRCCS "Burlo Garofolo" - Trieste, Trieste, Italy.
[Ti] Título:Lack of Prenylated Proteins, Autophagy Impairment and Apoptosis in SH-SY5Y Neuronal Cell Model of Mevalonate Kinase Deficiency.
[So] Source:Cell Physiol Biochem;41(4):1649-1660, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: Mevalonate Kinase Deficiency (MKD), is a hereditary disease due to mutations in mevalonate kinase gene (MVK). MKD has heterogeneous clinical phenotypes: the correlation between MVK mutations and MKD clinical phenotype is still to be fully elucidated. Deficiency of prenylated proteins has been hypothesized as possible MKD pathogenic mechanism. Based on this hypothesis and considering that neurologic impairment characterizes Mevalonic Aciduria (MA), the most severe form of MKD, we studied the effects of I268T and N301T MVK mutations on protein prenylation, autophagy and programmed cell death in SH-SY5Y neuroblastoma cell lines. METHODS: SH-SY5Y cells were transiently transfected, with the pCMV-6 plasmid containing MVK wild type and the two mutated sequences. Protein prenylation levels were evaluated using GFP-RhoA-F to assess farnesylation, and GFP-RhoA to evaluate geranylgeranylation; autophagy was measured by evaluating LC3 and p62 protein levels, while Annexin V-FITC and Propidium Iodide staining allowed apoptosis detection. RESULTS: MVK mutants' over-expression causes decreased levels of farnesylation and geranylgeranylation, and also increased LC3 lipidation in SH-SY5Y, with concomitant p62 accumulation. Treatment with bafilomycin A1 (an inhibitor of vacuolar H+-ATPase, a late autophagy inhibitor) further increase LC3-II and p62 levels, suggesting that degradation of autophagolysosome could be impaired. SH-SY5Y, with both MVK mutants, showed apoptosis increase; the presence of N301T associated with augmented cell death. CONCLUSIONS: We hypothesize that mevalonate pathway impairment causes alteration of farnesylation and geranylgeranylation proteins and alteration of the autophagic flux; these changes can induce apoptosis, possibly more relevant in the presence of N301T mutation.
[Mh] Termos MeSH primário: Apoptose
Autofagia
Deficiência de Mevalonato Quinase/metabolismo
Modelos Biológicos
Prenilação de Proteína
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Macrolídeos/farmacologia
Deficiência de Mevalonato Quinase/genética
Deficiência de Mevalonato Quinase/patologia
Proteínas Associadas aos Microtúbulos/genética
Proteínas Associadas aos Microtúbulos/metabolismo
Mutação
Fosfotransferases (Aceptor do Grupo Álcool)/genética
Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (LC3 protein, rat); 0 (Macrolides); 0 (Microtubule-Associated Proteins); 88899-55-2 (bafilomycin A1); EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)); EC 2.7.1.36 (mevalonate kinase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170621
[Lr] Data última revisão:
170621
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170331
[St] Status:MEDLINE
[do] DOI:10.1159/000471235


  10 / 1848 MEDLINE  
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Texto completo
[PMID]:28235469
[Au] Autor:Noguera-Salvà MA; Guardiola-Serrano F; Martin ML; Marcilla-Etxenike A; Bergo MO; Busquets X; Escribá PV
[Ad] Endereço:Laboratory of Molecular Cell Biomedicine, Department of Biology, University of the Balearic Islands, E-07122 Palma, Balearic Islands, Spain.
[Ti] Título:Role of the C-terminal basic amino acids and the lipid anchor of the Gγ protein in membrane interactions and cell localization.
[So] Source:Biochim Biophys Acta;1859(9 Pt B):1536-1547, 2017 09.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Heterotrimeric G proteins are peripheral membrane proteins that frequently localize to the plasma membrane where their presence in molar excess over G protein coupled receptors permits signal amplification. Their distribution is regulated by protein-lipid interactions, which has a clear influence on their activity. Gßγ dimer drives the interaction between G protein heterotrimers with cell membranes. We focused our study on the role of the C-terminal region of the Gγ protein in G protein interactions with cell membranes. The Gγ subunit is modified at cysteine (Cys) 68 by the addition of an isoprenyl lipid, which is followed by the proteolytic removal of the last three residues that leaves an isoprenylated and carboxyl methylated Cys-68 as the terminal amino acid. The role of Cys isoprenylation of the CAAX box has been defined for other proteins, yet the importance of proteolysis and carboxyl methylation of isoprenylated proteins is less clear. Here, we showed that not only geranylgeranylation but also proteolysis and carboxyl methylation are essential for the correct localization of Gγ in the plasma membrane. Moreover, we showed the importance of electrostatic interactions between the inner leaflet of the plasma membrane and the positively charged C-terminal domain of the Gγ subunit (amino acids Arg-62, Lys-64 and Lys-65) as a second signal to reach the plasma membrane. Indeed, single or multiple point mutations at Gγ C-terminal amino acids have a significant effect on Gγ protein-plasma membrane interactions and its localization to charged Ld (liquid disordered) membrane microdomains. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá.
[Mh] Termos MeSH primário: Membrana Celular/química
Subunidades gama da Proteína de Ligação ao GTP/química
Lipídeos de Membrana/química
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Linhagem Celular Tumoral
Diterpenos/metabolismo
Subunidades gama da Proteína de Ligação ao GTP/análise
Seres Humanos
Ligação Proteica
Prenilação de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Diterpenes); 0 (GTP-Binding Protein gamma Subunits); 0 (Membrane Lipids); 83807-40-3 (geranylgeranic acid)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170226
[St] Status:MEDLINE



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