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  1 / 20643 MEDLINE  
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[PMID]:29374258
[Au] Autor:Hirata T; Mishra SK; Nakamura S; Saito K; Motooka D; Takada Y; Kanzawa N; Murakami Y; Maeda Y; Fujita M; Yamaguchi Y; Kinoshita T
[Ad] Endereço:Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871, Japan.
[Ti] Título:Identification of a Golgi GPI-N-acetylgalactosamine transferase with tandem transmembrane regions in the catalytic domain.
[So] Source:Nat Commun;9(1):405, 2018 01 26.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Many eukaryotic proteins are anchored to the cell surface via the glycolipid glycosylphosphatidylinositol (GPI). Mammalian GPIs have a conserved core but exhibit diverse N-acetylgalactosamine (GalNAc) modifications, which are added via a yet unresolved process. Here we identify the Golgi-resident GPI-GalNAc transferase PGAP4 and show by mass spectrometry that PGAP4 knockout cells lose GPI-GalNAc structures. Furthermore, we demonstrate that PGAP4, in contrast to known Golgi glycosyltransferases, is not a single-pass membrane protein but contains three transmembrane domains, including a tandem transmembrane domain insertion into its glycosyltransferase-A fold as indicated by comparative modeling. Mutational analysis reveals a catalytic site, a DXD-like motif for UDP-GalNAc donor binding, and several residues potentially involved in acceptor binding. We suggest that a juxtamembrane region of PGAP4 accommodates various GPI-anchored proteins, presenting their acceptor residue toward the catalytic center. In summary, we present insights into the structure of PGAP4 and elucidate the initial step of GPI-GalNAc biosynthesis.
[Mh] Termos MeSH primário: Acetilgalactosamina/química
Glicosilfosfatidilinositóis/química
Complexo de Golgi/metabolismo
N-Acetilgalactosaminiltransferases/química
[Mh] Termos MeSH secundário: Acetilgalactosamina/biossíntese
Motivos de Aminoácidos
Animais
Células CHO
Domínio Catalítico
Cricetulus
Cristalografia por Raios X
Expressão Gênica
Vetores Genéticos/química
Vetores Genéticos/metabolismo
Glicosilfosfatidilinositóis/metabolismo
Complexo de Golgi/ultraestrutura
Seres Humanos
Camundongos
Camundongos Knockout
Modelos Moleculares
Mutação
N-Acetilgalactosaminiltransferases/genética
N-Acetilgalactosaminiltransferases/metabolismo
Ligação Proteica
Conformação Proteica em alfa-Hélice
Conformação Proteica em Folha beta
Domínios e Motivos de Interação entre Proteínas
Homologia Estrutural de Proteína
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Glycosylphosphatidylinositols); EC 2.4.1.- (N-Acetylgalactosaminyltransferases); EC 2.4.1.41 (polypeptide N-acetylgalactosaminyltransferase); KM15WK8O5T (Acetylgalactosamine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180128
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02799-0


  2 / 20643 MEDLINE  
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[PMID]:29177331
[Au] Autor:Ray A; Gräter F; Thukral L
[Ad] Endereço:CSIR-Institute of Genomics and Integrative Biology, Mathura Road, New Delhi, 110025, India. lipi.thukral@igib.res.in.
[Ti] Título:Probing molecular forces in multi-component physiological membranes.
[So] Source:Phys Chem Chem Phys;20(4):2155-2161, 2018 Jan 24.
[Is] ISSN:1463-9084
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Biological membranes are remarkably heterogeneous, composed of diverse lipid mixtures with distinct chemical structure and composition. By combining molecular dynamics simulations and the newly developed Lipid-Force Distribution Analysis (L-FDA), we explore force transmission in complex multi-component membrane models mimicking eukaryotic organelles. We found that the chemical-moiety based segmentation at membrane interfaces revealed a distinctive distribution of bonded and non-bonded forces in diverse membrane environment. Our molecular stress analysis could have far-reaching implications in describing the relationship between membrane mechanical properties and functional states of chemically distinct lipids.
[Mh] Termos MeSH primário: Bicamadas Lipídicas/química
[Mh] Termos MeSH secundário: Algoritmos
Análise por Conglomerados
Retículo Endoplasmático/química
Complexo de Golgi/química
Bicamadas Lipídicas/metabolismo
Mitocôndrias/química
Simulação de Dinâmica Molecular
Fosfatidilcolinas/química
Fosfatidiletanolaminas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lipid Bilayers); 0 (Phosphatidylcholines); 0 (Phosphatidylethanolamines); 10015-88-0 (1-palmitoyl-2-oleoylphosphatidylethanolamine); TE895536Y5 (1-palmitoyl-2-oleoylphosphatidylcholine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1039/c7cp05981g


  3 / 20643 MEDLINE  
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[PMID]:28449094
[Au] Autor:Ehrhardt N; Doche ME; Chen S; Mao HZ; Walsh MT; Bedoya C; Guindi M; Xiong W; Ignatius Irudayam J; Iqbal J; Fuchs S; French SW; Mahmood Hussain M; Arditi M; Arumugaswami V; Péterfy M
[Ad] Endereço:Department of Basic Medical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA.
[Ti] Título:Hepatic Tm6sf2 overexpression affects cellular ApoB-trafficking, plasma lipid levels, hepatic steatosis and atherosclerosis.
[So] Source:Hum Mol Genet;26(14):2719-2731, 2017 07 15.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The human transmembrane 6 superfamily member 2 (TM6SF2) gene has been implicated in plasma lipoprotein metabolism, alcoholic and non-alcoholic fatty liver disease and myocardial infarction in multiple genome-wide association studies. To investigate the role of Tm6sf2 in metabolic homeostasis, we generated mice with elevated expression using adeno-associated virus (AAV)-mediated gene delivery. Hepatic overexpression of mouse Tm6sf2 resulted in phenotypes previously observed in Tm6sf2-deficient mice including reduced plasma lipid levels, diminished hepatic triglycerides secretion and increased hepatosteatosis. Furthermore, increased hepatic Tm6sf2 expression protected against the development of atherosclerosis in LDL-receptor/ApoB48-deficient mice. In cultured human hepatocytes, Tm6sf2 overexpression reduced apolipoprotein B secretion and resulted in its accumulation within the endoplasmic reticulum (ER) suggesting impaired ER-to-Golgi trafficking of pre-very low-density lipoprotein (VLDL) particles. Analysis of two metabolic trait-associated coding polymorphisms in the human TM6SF2 gene (rs58542926 and rs187429064) revealed that both variants impact TM6SF2 expression by affecting the rate of protein turnover. These data demonstrate that rs58542926 (E167K) and rs187429064 (L156P) are functional variants and suggest that they influence metabolic traits through altered TM6SF2 protein stability. Taken together, our results indicate that cellular Tm6sf2 level is an important determinant of VLDL metabolism and further implicate TM6SF2 as a causative gene underlying metabolic disease and trait associations at the 19p13.11 locus.
[Mh] Termos MeSH primário: Apolipoproteínas B/metabolismo
Aterosclerose/metabolismo
Fígado/metabolismo
Proteínas de Membrana/biossíntese
Hepatopatia Gordurosa não Alcoólica/metabolismo
[Mh] Termos MeSH secundário: Animais
Apolipoproteínas B/genética
Aterosclerose/sangue
Aterosclerose/genética
Células Cultivadas
Retículo Endoplasmático/metabolismo
Feminino
Estudo de Associação Genômica Ampla
Complexo de Golgi/metabolismo
Células Hep G2
Hepatócitos/metabolismo
Seres Humanos
Lipoproteínas/sangue
Masculino
Proteínas de Membrana/genética
Proteínas de Membrana/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Hepatopatia Gordurosa não Alcoólica/sangue
Hepatopatia Gordurosa não Alcoólica/genética
Polimorfismo de Nucleotídeo Único
Transporte Proteico
Triglicerídeos/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Apolipoproteins B); 0 (Lipoproteins); 0 (Membrane Proteins); 0 (TM6SF2 protein, human); 0 (Triglycerides)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180225
[Lr] Data última revisão:
180225
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170428
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddx159


  4 / 20643 MEDLINE  
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[PMID]:29300766
[Au] Autor:Wu Y; Guo XP; Kanemoto S; Maeoka Y; Saito A; Asada R; Matsuhisa K; Ohtake Y; Imaizumi K; Kaneko M
[Ad] Endereço:Department of Biochemistry, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
[Ti] Título:Sec16A, a key protein in COPII vesicle formation, regulates the stability and localization of the novel ubiquitin ligase RNF183.
[So] Source:PLoS One;13(1):e0190407, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We identified 37 ubiquitin ligases containing RING-finger and transmembrane domains. Of these, we found that RNF183 is abundantly expressed in the kidney. RNF183 predominantly localizes to the endoplasmic reticulum (ER), Golgi, and lysosome. We identified Sec16A, which is involved in coat protein complex II vesicle formation, as an RNF183-interacting protein. RNF183 colocalized with Sec16A and interacted through the central conserved domain (CCD) of Sec16A. Although Sec16A is not a substrate for RNF183, RNF183 was more rapidly degraded by the ER-associated degradation (ERAD) in the absence of Sec16A. Sec16A also stabilized the interacting ubiquitin ligase RNF152, which localizes to the lysosome and has structural similarity with RNF183. These results suggest that Sec16A appears to regulate the protein stability and localization of lysosomal ubiquitin ligases.
[Mh] Termos MeSH primário: Vesículas Revestidas pelo Complexo de Proteína do Envoltório/metabolismo
Ubiquitina-Proteína Ligases/metabolismo
Proteínas de Transporte Vesicular/fisiologia
[Mh] Termos MeSH secundário: Retículo Endoplasmático/metabolismo
Complexo de Golgi/metabolismo
Seres Humanos
Lisossomos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (SEC16A protein, human); 0 (Vesicular Transport Proteins); EC 2.3.2.27 (RNF183 protein, human); EC 2.3.2.27 (Ubiquitin-Protein Ligases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180105
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190407


  5 / 20643 MEDLINE  
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[PMID]:28465429
[Au] Autor:Wesolowski J; Weber MM; Nawrotek A; Dooley CA; Calderon M; St Croix CM; Hackstadt T; Cherfils J; Paumet F
[Ad] Endereço:Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
[Ti] Título: Hijacks ARF GTPases To Coordinate Microtubule Posttranslational Modifications and Golgi Complex Positioning.
[So] Source:MBio;8(3), 2017 May 02.
[Is] ISSN:2150-7511
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The intracellular bacterium develops in a parasitic compartment called the inclusion. Posttranslationally modified microtubules encase the inclusion, controlling the positioning of Golgi complex fragments around the inclusion. The molecular mechanisms by which coopts the host cytoskeleton and the Golgi complex to sustain its infectious compartment are unknown. Here, using a genetically modified strain, we discovered that both posttranslationally modified microtubules and Golgi complex positioning around the inclusion are controlled by the chlamydial inclusion protein CT813/CTL0184/InaC and host ARF GTPases. CT813 recruits ARF1 and ARF4 to the inclusion membrane, where they induce posttranslationally modified microtubules. Similarly, both ARF isoforms are required for the repositioning of Golgi complex fragments around the inclusion. We demonstrate that CT813 directly recruits ARF GTPases on the inclusion membrane and plays a pivotal role in their activation. Together, these results reveal that uses CT813 to hijack ARF GTPases to couple posttranslationally modified microtubules and Golgi complex repositioning at the inclusion. is an important cause of morbidity and a significant economic burden in the world. However, how develops its intracellular compartment, the so-called inclusion, is poorly understood. Using genetically engineered mutants, we discovered that the effector protein CT813 recruits and activates host ADP-ribosylation factor 1 (ARF1) and ARF4 to regulate microtubules. In this context, CT813 acts as a molecular platform that induces the posttranslational modification of microtubules around the inclusion. These cages are then used to reposition the Golgi complex during infection and promote the development of the inclusion. This study provides the first evidence that ARF1 and ARF4 play critical roles in controlling posttranslationally modified microtubules around the inclusion and that hijacks this novel function of ARF to reposition the Golgi complex.
[Mh] Termos MeSH primário: Proteínas de Bactérias/metabolismo
Chlamydia trachomatis/metabolismo
GTP Fosfo-Hidrolases/metabolismo
Complexo de Golgi/metabolismo
Microtúbulos/metabolismo
[Mh] Termos MeSH secundário: Fator 1 de Ribosilação do ADP/metabolismo
Fatores de Ribosilação do ADP/metabolismo
Actinas
Proteínas de Bactérias/genética
Chlamydia trachomatis/genética
Complexo de Golgi/ultraestrutura
Células HeLa
Interações Hospedeiro-Patógeno
Seres Humanos
Corpos de Inclusão/microbiologia
Microtúbulos/genética
Processamento de Proteína Pós-Traducional
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Actins); 0 (Bacterial Proteins); EC 3.6.1.- (GTP Phosphohydrolases); EC 3.6.5.2 (ADP-Ribosylation Factor 1); EC 3.6.5.2 (ADP-Ribosylation Factors); EC 3.6.5.2 (ARF4 protein, human)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180126
[Lr] Data última revisão:
180126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE


  6 / 20643 MEDLINE  
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[PMID]:29244877
[Au] Autor:Steinmann ME; Schmidt RS; Macêdo JP; Kunz Renggli C; Bütikofer P; Rentsch D; Mäser P; Sigel E
[Ad] Endereço:Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.
[Ti] Título:Identification and characterization of the three members of the CLC family of anion transport proteins in Trypanosoma brucei.
[So] Source:PLoS One;12(12):e0188219, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:CLC type anion transport proteins are homo-dimeric or hetero-dimeric with an integrated transport function in each subunit. We have identified and partially characterized three members of this family named TbVCL1, TbVCL2 and TbVCL3 in Trypanosoma brucei. Among the human CLC family members, the T. brucei proteins display highest similarity to CLC-6 and CLC-7. TbVCL1, but not TbVCL2 and TbVCL3 is able to complement growth of a CLC-deficient Saccharomyces cerevisiae mutant. All TbVCL-HA fusion proteins localize intracellulary in procyclic form trypanosomes. TbVCL1 localizes close to the Golgi apparatus and TbVCL2 and TbVCL3 to the endoplasmic reticulum. Upon expression in Xenopus oocytes, all three proteins induce similar outward rectifying chloride ion currents. Currents are sensitive to low concentrations of DIDS, insensitive to the pH in the range 5.4 to 8.4 and larger in nitrate than in chloride medium.
[Mh] Termos MeSH primário: Canais de Cloreto/genética
Retículo Endoplasmático/metabolismo
Estágios do Ciclo de Vida/fisiologia
Proteínas de Protozoários/genética
Saccharomyces cerevisiae/metabolismo
Trypanosoma brucei brucei/metabolismo
[Mh] Termos MeSH secundário: Ácido 4,4'-Di-Isotiocianoestilbeno-2,2'-Dissulfônico/farmacologia
Animais
Canais de Cloreto/antagonistas & inibidores
Canais de Cloreto/metabolismo
Cloretos/metabolismo
Retículo Endoplasmático/ultraestrutura
Feminino
Expressão Gênica
Teste de Complementação Genética
Complexo de Golgi/metabolismo
Complexo de Golgi/ultraestrutura
Seres Humanos
Transporte de Íons
Potenciais da Membrana/efeitos dos fármacos
Potenciais da Membrana/fisiologia
Nitratos/metabolismo
Oócitos/citologia
Oócitos/efeitos dos fármacos
Oócitos/metabolismo
Técnicas de Patch-Clamp
Multimerização Proteica
Proteínas de Protozoários/antagonistas & inibidores
Proteínas de Protozoários/metabolismo
Saccharomyces cerevisiae/genética
Trypanosoma brucei brucei/crescimento & desenvolvimento
Trypanosoma brucei brucei/ultraestrutura
Xenopus laevis
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CLCN6 protein, human); 0 (CLCN7 protein, human); 0 (Chloride Channels); 0 (Chlorides); 0 (Nitrates); 0 (Protozoan Proteins); Q1O6DSW23R (4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171216
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188219


  7 / 20643 MEDLINE  
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[PMID]:29184172
[Au] Autor:Fromme JC; Munson M
[Ad] Endereço:Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, New York 14853, USA.
[Ti] Título:Capturing endosomal vesicles at the Golgi.
[So] Source:Nat Cell Biol;19(12):1384-1386, 2017 Nov 29.
[Is] ISSN:1476-4679
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Membrane trafficking specificity between distinct compartments ensures that cargo proteins and lipids are delivered to their target organelle. However, accurate recognition of cargo carriers by tethering factors on target membranes is poorly understood. TBC1D23 is now identified as an adaptor that links endosome-derived vesicles with golgins at the trans-Golgi.
[Mh] Termos MeSH primário: Endossomos/metabolismo
Complexo de Golgi/metabolismo
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Proteínas Ativadoras de GTPase/metabolismo
Proteínas de Membrana/metabolismo
Modelos Biológicos
Rede trans-Golgi/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (GTPase-Activating Proteins); 0 (Membrane Proteins)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171219
[Lr] Data última revisão:
171219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171130
[St] Status:MEDLINE
[do] DOI:10.1038/ncb3649


  8 / 20643 MEDLINE  
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[PMID]:28450044
[Au] Autor:Simm R; Kvalvaag AS; van Deurs B; Lindbäck T; Sandvig K
[Ad] Endereço:Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Molecular Cell Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
[Ti] Título:Benzyl alcohol induces a reversible fragmentation of the Golgi apparatus and inhibits membrane trafficking between endosomes and the trans-Golgi network.
[So] Source:Exp Cell Res;357(1):67-78, 2017 08 01.
[Is] ISSN:1090-2422
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Benzyl alcohol (BnOH) is widely used as a component of foods, cosmetics, household products and medical products. It is generally considered to be safe for human use, however, it has been connected to a number of adverse effects, including hypersensitivity reactions and neonatal deaths. BnOH is a membrane fluidizing agent that can affect membrane protein activity and cellular processes such as ligand binding to cell surface receptors, endocytosis and degradation of lysosomal cargo. In this study, we examined the effects of BnOH on intracellular transport using Shiga toxin (Stx), diphtheria toxin (DT) and ricin. BnOH caused reduced toxicity of all three toxins at BnOH concentrations that cause membrane fluidization. The reduced toxicity of Stx and ricin was mainly due to inhibition of retrograde transport between endosomes and the trans-Golgi network as BnOH had small effects on cell association and endocytosis of ricin and Stx. Strikingly, BnOH also induced a reversible fragmentation of the Golgi apparatus.
[Mh] Termos MeSH primário: Álcool Benzílico/farmacologia
Transporte Biológico/efeitos dos fármacos
Endossomos/efeitos dos fármacos
Complexo de Golgi/efeitos dos fármacos
Rede trans-Golgi/efeitos dos fármacos
[Mh] Termos MeSH secundário: Movimento Celular/efeitos dos fármacos
Endocitose/efeitos dos fármacos
Endossomos/metabolismo
Complexo de Golgi/metabolismo
Células HeLa
Seres Humanos
Transporte Proteico/efeitos dos fármacos
Toxina Shiga/metabolismo
Rede trans-Golgi/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
75757-64-1 (Shiga Toxin); LKG8494WBH (Benzyl Alcohol)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171209
[Lr] Data última revisão:
171209
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE


  9 / 20643 MEDLINE  
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[PMID]:28740133
[Au] Autor:Konitsiotis AD; Roßmannek L; Stanoev A; Schmick M; Bastiaens PIH
[Ad] Endereço:Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, 44227, Germany.
[Ti] Título:Spatial cycles mediated by UNC119 solubilisation maintain Src family kinases plasma membrane localisation.
[So] Source:Nat Commun;8(1):114, 2017 07 24.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The peripheral membrane proto-oncogene Src family protein tyrosine kinases relay growth factor signals to the cytoplasm of mammalian cells. We unravel the spatial cycles of solubilisation, trapping on perinuclear membrane compartments and vesicular transport that counter entropic equilibration to endomembranes for maintaining the enrichment and activity of Src family protein tyrosine kinases at the plasma membrane. The solubilising factor UNC119 sequesters myristoylated Src family protein tyrosine kinases from the cytoplasm, enhancing their diffusion to effectively release Src family protein tyrosine kinases on the recycling endosome by localised Arl2/3 activity. Src is then trapped on the recycling endosome via electrostatic interactions, whereas Fyn is quickly released to be kinetically trapped on the Golgi by palmitoyl acyl-transferase activity. Vesicular trafficking from these compartments restores enrichment of the Src family protein tyrosine kinases to the plasma membrane. Interference with these spatial cycles by UNC119 knockdown disrupts Src family protein tyrosine kinase localisation and signalling activity, indicating that UNC119 could be a drug target to affect oncogenic Src family protein tyrosine kinase signalling.The peripheral membrane proto-oncogene Src family protein tyrosine kinases (SFKs) transmit growth factor signals to the cytoplasm. Here the authors show that the solubilising factor UNC119 sequesters myristoylated SFKs to maintain its enrichment at the plasma membrane to enable signal transduction.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Membrana Celular/metabolismo
Transdução de Sinais
Quinases da Família src/metabolismo
[Mh] Termos MeSH secundário: Fatores de Ribosilação do ADP/genética
Fatores de Ribosilação do ADP/metabolismo
Proteínas Adaptadoras de Transdução de Sinal/química
Proteínas Adaptadoras de Transdução de Sinal/genética
Linhagem Celular
Endossomos/metabolismo
Proteínas de Ligação ao GTP/genética
Proteínas de Ligação ao GTP/metabolismo
Complexo de Golgi/metabolismo
Células HT29
Células HeLa
Seres Humanos
Immunoblotting
Microscopia Confocal
Modelos Biológicos
Ácido Mirístico/metabolismo
Ligação Proteica
Proteínas Proto-Oncogênicas c-fyn/genética
Proteínas Proto-Oncogênicas c-fyn/metabolismo
Interferência de RNA
Solubilidade
Quinases da Família src/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (UNC119 protein, human); 0I3V7S25AW (Myristic Acid); EC 2.7.10.2 (Proto-Oncogene Proteins c-fyn); EC 2.7.10.2 (src-Family Kinases); EC 3.6.1.- (ARL2 protein, human); EC 3.6.1.- (GTP-Binding Proteins); EC 3.6.5.2 (ADP-Ribosylation Factors); EC 3.6.5.2 (ARL3 protein, human)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-00116-3


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[PMID]:29020060
[Au] Autor:Royal AA; Tinker A; Harmer SC
[Ad] Endereço:William Harvey Research Institute, The Heart Centre, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
[Ti] Título:Phosphatidylinositol-4,5-bisphosphate is required for KCNQ1/KCNE1 channel function but not anterograde trafficking.
[So] Source:PLoS One;12(10):e0186293, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The slow delayed-rectifier potassium current (IKs) is crucial for human cardiac action potential repolarization. The formation of IKs requires co-assembly of the KCNQ1 α-subunit and KCNE1 ß-subunit, and mutations in either of these subunits can lead to hereditary long QT syndrome types 1 and 5, respectively. It is widely recognised that the KCNQ1/KCNE1 (Q1/E1) channel requires phosphatidylinositol-4,5-bisphosphate (PIP2) binding for function. We previously identified a cluster of basic residues in the proximal C-terminus of KCNQ1 that form a PIP2/phosphoinositide binding site. Upon charge neutralisation of these residues we found that the channel became more retained in the endoplasmic reticulum, which raised the possibility that channel-phosphoinositide interactions could play a role in channel trafficking. To explore this further we used a chemically induced dimerization (CID) system to selectively deplete PIP2 and/or phosphatidylinositol-4-phosphate (PI(4)P) at the plasma membrane (PM) or Golgi, and we subsequently monitored the effects on both channel trafficking and function. The depletion of PIP2 and/or PI(4)P at either the PM or Golgi did not alter channel cell-surface expression levels. However, channel function was extremely sensitive to the depletion of PIP2 at the PM, which is in contrast to the response of other cardiac potassium channels tested (Kir2.1 and Kv11.1). Surprisingly, when using the CID system IKs was dramatically reduced even before dimerization was induced, highlighting limitations regarding the utility of this system when studying processes highly sensitive to PIP2 depletion. In conclusion, we identify that the Q1/E1 channel does not require PIP2 or PI(4)P for anterograde trafficking, but is heavily reliant on PIP2 for channel function once at the PM.
[Mh] Termos MeSH primário: Canal de Potássio KCNQ1/metabolismo
Fosfatidilinositol 4,5-Difosfato/metabolismo
Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo
[Mh] Termos MeSH secundário: Animais
Células CHO
Membrana Celular/efeitos dos fármacos
Membrana Celular/metabolismo
Cricetinae
Cricetulus
Retículo Endoplasmático/efeitos dos fármacos
Retículo Endoplasmático/metabolismo
Genes Reporter
Complexo de Golgi/efeitos dos fármacos
Complexo de Golgi/metabolismo
Células HEK293
Seres Humanos
Ativação do Canal Iônico/efeitos dos fármacos
Mutação/genética
Ligação Proteica/efeitos dos fármacos
Multimerização Proteica/efeitos dos fármacos
Transporte Proteico/efeitos dos fármacos
Sirolimo/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (KCNE1 protein, human); 0 (KCNQ1 Potassium Channel); 0 (Phosphatidylinositol 4,5-Diphosphate); 0 (Potassium Channels, Voltage-Gated); W36ZG6FT64 (Sirolimus)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171012
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0186293



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