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[PMID]:29428127
[Au] Autor:Liao J; Liu X; Gao M; Wang M; Wang Y; Wang F; Huang W; Liu G
[Ad] Endereço:Department of Cardiology, Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian 116011, China; Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking University Health Science Center,
[Ti] Título:Dyslipidemia, steatohepatitis and atherogenesis in lipodystrophic apoE deficient mice with Seipin deletion.
[So] Source:Gene;648:82-88, 2018 Mar 30.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:SEIPIN is an integral membrane protein located in the endoplasmic reticulum, regulating adipocytes differentiation and lipolysis. Deficiency of Seipin in mice causes severe general lipodystrophy, accompanied by insulin resistance, postprandial hypertriglyceridemia and steatohepatitis. In atherosclerosis-prone Ldlr null (Ldlr ) mice, lipodystrophy caused by Seipin deletion even led to severe hypercholesteremia and accelerated atherogenesis, when challenged with an atherogenic diet. However, whether the phenotypes observed in Seipin Ldlr mice were a common consequence due to lipodystrophy, rather than genetic background restricted or diet dependent, was unknown. Herein we explored the lipodystrophy-related dyslipidemia, steatohepatitis and atherogenesis in another atherosclerosis-prone murine model, apolipoprotein E null (apoE ) mice. Besides, we also compared phenotypes between sexes in apoE mice with Seipin deletion (Seipin apoE ). We found that compared with apoE controls, Seipin apoE mice also developed severe general lipodystrophy with hyperlipidemia, steatohepatitis and increased atherogenesis. Although the severity of adipose loss in female and male Seipin apoE mice were similar, hyperlipidemia, steatohepatitis and atherosclerosis were less severe in females than in males. Therefore, we demonstrated that lipodystrophy-related metabolic disorders, caused by Seipin deletion, were independent of genetic background and experimental diet, as seen in Ldlr and apoE mice. However, gender factor affected the disease progression, with females more resistant to developing lipodystrophy-related metabolic consequences.
[Mh] Termos MeSH primário: Apolipoproteínas E/genética
Aterosclerose/genética
Dislipidemias/genética
Fígado Gorduroso/genética
Proteínas Heterotriméricas de Ligação ao GTP/genética
Lipodistrofia/genética
[Mh] Termos MeSH secundário: Animais
Apolipoproteínas E/deficiência
Aterosclerose/metabolismo
Aterosclerose/patologia
Progressão da Doença
Dislipidemias/metabolismo
Dislipidemias/patologia
Fígado Gorduroso/metabolismo
Fígado Gorduroso/patologia
Feminino
Proteínas Heterotriméricas de Ligação ao GTP/deficiência
Lipodistrofia/metabolismo
Lipodistrofia/patologia
Masculino
Camundongos Endogâmicos C57BL
Camundongos Knockout
Receptores de LDL/deficiência
Receptores de LDL/genética
Índice de Gravidade de Doença
Fatores Sexuais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apolipoproteins E); 0 (Bscl2 protein, mouse); 0 (Receptors, LDL); EC 3.6.5.1 (Heterotrimeric GTP-Binding Proteins)
[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:180212
[St] Status:MEDLINE


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[PMID]:29206867
[Au] Autor:Ozdemir AC; Wynn GM; Vester A; Weitzmann MN; Neigh GN; Srinivasan S; Rudd MK
[Ad] Endereço:Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States of America.
[Ti] Título:GNB3 overexpression causes obesity and metabolic syndrome.
[So] Source:PLoS One;12(12):e0188763, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The G-protein beta subunit 3 (GNB3) gene has been implicated in obesity risk; however, the molecular mechanism of GNB3-related disease is unknown. GNB3 duplication is responsible for a syndromic form of childhood obesity, and an activating DNA sequence variant (C825T) in GNB3 is also associated with obesity. To test the hypothesis that GNB3 overexpression causes obesity, we created bacterial artificial chromosome (BAC) transgenic mice that carry an extra copy of the human GNB3 risk allele. Here we show that GNB3-T/+ mice have increased adiposity, but not greater food intake or a defect in satiety. GNB3-T/+ mice have elevated fasting plasma glucose, insulin, and C-peptide, as well as glucose intolerance, indicating type 2 diabetes. Fasting plasma leptin, triglycerides, cholesterol and phospholipids are elevated, suggesting metabolic syndrome. Based on a battery of behavioral tests, GNB3-T/+ mice did not exhibit anxiety- or depressive-like phenotypes. GNB3-T/+ and wild-type animals have similar activity levels and heat production; however, GNB3-T/+ mice exhibit dysregulation of acute thermogenesis. Finally, Ucp1 expression is significantly lower in white adipose tissue (WAT) in GNB3-T/+ mice, suggestive of WAT remodeling that could lead to impaired cellular thermogenesis. Taken together, our study provides the first functional link between GNB3 and obesity, and presents insight into novel pathways that could be applied to combat obesity and type 2 diabetes.
[Mh] Termos MeSH primário: Proteínas Heterotriméricas de Ligação ao GTP/metabolismo
Síndrome Metabólica/metabolismo
Obesidade/metabolismo
[Mh] Termos MeSH secundário: Animais
Feminino
Seres Humanos
Masculino
Camundongos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (guanine nucleotide binding protein (G protein), beta polypeptide 3, human); EC 3.6.5.1 (Heterotrimeric GTP-Binding Proteins)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171229
[Lr] Data última revisão:
171229
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171206
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188763


  3 / 2649 MEDLINE  
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[PMID]:28887436
[Au] Autor:Chen C; Barbieri JT
[Ad] Endereço:From the Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
[Ti] Título:When doesn't fit the mold: A pertussis-like toxin with altered specificity.
[So] Source:J Biol Chem;292(36):15159-15160, 2017 Sep 08.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Bacterial toxins introduce protein modifications such as ADP-ribosylation to manipulate host cell signaling and physiology. Several general mechanisms for toxin function have been established, but the extent to which previously uncharacterized toxins utilize these mechanisms is unknown. A study of an pertussis-like toxin demonstrates that this protein acts on a known toxin substrate but displays distinct and dual chemoselectivity, suggesting this pertussis-like toxin may serve as a unique tool to study G-protein signaling in eukaryotic cells.
[Mh] Termos MeSH primário: Toxinas Bacterianas/química
Toxinas Bacterianas/farmacologia
Escherichia coli/química
Proteínas Heterotriméricas de Ligação ao GTP/antagonistas & inibidores
Toxina Pertussis/química
[Mh] Termos MeSH secundário: Animais
Células Eucarióticas/efeitos dos fármacos
Células Eucarióticas/metabolismo
Proteínas Heterotriméricas de Ligação ao GTP/metabolismo
Seres Humanos
Modelos Moleculares
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Toxins); EC 2.4.2.31 (Pertussis Toxin); EC 3.6.5.1 (Heterotrimeric GTP-Binding Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170910
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.H117.796094


  4 / 2649 MEDLINE  
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[PMID]:28663369
[Au] Autor:Littler DR; Ang SY; Moriel DG; Kocan M; Kleifeld O; Johnson MD; Tran MT; Paton AW; Paton JC; Summers RJ; Schembri MA; Rossjohn J; Beddoe T
[Ad] Endereço:From the Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
[Ti] Título:Structure-function analyses of a pertussis-like toxin from pathogenic reveal a distinct mechanism of inhibition of trimeric G-proteins.
[So] Source:J Biol Chem;292(36):15143-15158, 2017 Sep 08.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pertussis-like toxins are secreted by several bacterial pathogens during infection. They belong to the AB virulence factors, which bind to glycans on host cell membranes for internalization. Host cell recognition and internalization are mediated by toxin B subunits sharing a unique pentameric ring-like assembly. Although the role of pertussis toxin in whooping cough is well-established, pertussis-like toxins produced by other bacteria are less studied, and their mechanisms of action are unclear. Here, we report that some extra-intestinal pathogens ( those that reside in the gut but can spread to other bodily locations) encode a pertussis-like toxin that inhibits mammalian cell growth We found that this protein, Plt, is related to toxins produced by both nontyphoidal and typhoidal serovars. Pertussis-like toxins are secreted as disulfide-bonded heterohexamers in which the catalytic ADP-ribosyltransferase subunit is activated when exposed to the reducing environment in mammalian cells. We found here that the reduced Plt exhibits large structural rearrangements associated with its activation. We noted that inhibitory residues tethered within the NAD -binding site by an intramolecular disulfide in the oxidized state dissociate upon the reduction and enable loop restructuring to form the nucleotide-binding site. Surprisingly, although pertussis toxin targets a cysteine residue within the α subunit of inhibitory trimeric G-proteins, we observed that activated Plt toxin modifies a proximal lysine/asparagine residue instead. In conclusion, our results reveal the molecular mechanism underpinning activation of pertussis-like toxins, and we also identified differences in host target specificity.
[Mh] Termos MeSH primário: Toxinas Bacterianas/química
Toxinas Bacterianas/farmacologia
Escherichia coli/química
Proteínas Heterotriméricas de Ligação ao GTP/antagonistas & inibidores
Toxina Pertussis/química
[Mh] Termos MeSH secundário: Animais
Proliferação Celular/efeitos dos fármacos
Cercopithecus aethiops
Relação Dose-Resposta a Droga
Células Epiteliais/efeitos dos fármacos
Células HEK293
Proteínas Heterotriméricas de Ligação ao GTP/metabolismo
Seres Humanos
Modelos Moleculares
Relação Estrutura-Atividade
Células Vero
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Toxins); EC 2.4.2.31 (Pertussis Toxin); EC 3.6.5.1 (Heterotrimeric GTP-Binding Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170701
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.796094


  5 / 2649 MEDLINE  
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[PMID]:28615442
[Au] Autor:Pradhan S; Khatlani T; Nairn AC; Vijayan KV
[Ad] Endereço:From the Departments of Medicine.
[Ti] Título:The heterotrimeric G protein Gß interacts with the catalytic subunit of protein phosphatase 1 and modulates G protein-coupled receptor signaling in platelets.
[So] Source:J Biol Chem;292(32):13133-13142, 2017 Aug 11.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Thrombosis is caused by the activation of platelets at the site of ruptured atherosclerotic plaques. This activation involves engagement of G protein-coupled receptors (GPCR) on platelets that promote their aggregation. Although it is known that protein kinases and phosphatases modulate GPCR signaling, how serine/threonine phosphatases integrate with G protein signaling pathways is less understood. Because the subcellular localization and substrate specificity of the catalytic subunit of protein phosphatase 1 (PP1c) is dictated by PP1c-interacting proteins, here we sought to identify new PP1c interactors. GPCRs signal via the canonical heterotrimeric Gα and Gßγ subunits. Using a yeast two-hybrid screen, we discovered an interaction between PP1cα and the heterotrimeric G protein Gß subunit. Co-immunoprecipitation studies with epitope-tagged PP1c and Gß revealed that Gß interacts with the PP1c α, ß, and γ1 isoforms. Purified PP1c bound to recombinant Gß -GST protein, and PP1c co-immunoprecipitated with Gß in unstimulated platelets. Thrombin stimulation of platelets induced the dissociation of the PP1c-Gß complex, which correlated with an association of PP1c with phospholipase C ß3 (PLCß3), along with a concomitant dephosphorylation of the inhibitory Ser residue in PLCß3. siRNA-mediated depletion of (encoding Gß ) in murine megakaryocytes reduced protease-activated receptor 4, activating peptide-induced soluble fibrinogen binding. Thrombin-induced aggregation was decreased in PP1cα murine platelets and in human platelets treated with a small-molecule inhibitor of Gßγ. Finally, disruption of PP1c-Gß complexes with myristoylated Gß peptides containing the PP1c binding site moderately decreased thrombin-induced human platelet aggregation. These findings suggest that Gß protein enlists PP1c to modulate GPCR signaling in platelets.
[Mh] Termos MeSH primário: Plaquetas/metabolismo
Subunidades beta da Proteína de Ligação ao GTP/metabolismo
Megacariócitos/metabolismo
Modelos Moleculares
Fosfolipase C beta/metabolismo
Proteína Fosfatase 1/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Plaquetas/enzimologia
Células da Medula Óssea/citologia
Células da Medula Óssea/enzimologia
Células da Medula Óssea/metabolismo
Células Cultivadas
Cruzamentos Genéticos
Feminino
Subunidades beta da Proteína de Ligação ao GTP/química
Subunidades beta da Proteína de Ligação ao GTP/genética
Proteínas Heterotriméricas de Ligação ao GTP/antagonistas & inibidores
Proteínas Heterotriméricas de Ligação ao GTP/química
Proteínas Heterotriméricas de Ligação ao GTP/genética
Proteínas Heterotriméricas de Ligação ao GTP/metabolismo
Seres Humanos
Masculino
Megacariócitos/citologia
Megacariócitos/enzimologia
Camundongos Knockout
Camundongos Transgênicos
Mutagênese Sítio-Dirigida
Fosfolipase C beta/química
Fosfolipase C beta/genética
Agregação Plaquetária
Mutação Puntual
Domínios e Motivos de Interação entre Proteínas
Proteína Fosfatase 1/química
Proteína Fosfatase 1/genética
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Técnicas do Sistema de Duplo-Híbrido
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GTP-Binding Protein beta Subunits); 0 (Gnb1 protein, mouse); 0 (Recombinant Fusion Proteins); EC 3.1.3.16 (PPP1CA protein, mouse); EC 3.1.3.16 (Protein Phosphatase 1); EC 3.1.4.11 (Phospholipase C beta); EC 3.1.4.11 (Plcb3 protein, mouse); EC 3.6.5.1 (Heterotrimeric GTP-Binding Proteins)
[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:170616
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.796656


  6 / 2649 MEDLINE  
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[PMID]:28562590
[Au] Autor:Brockmann M; Blomen VA; Nieuwenhuis J; Stickel E; Raaben M; Bleijerveld OB; Altelaar AFM; Jae LT; Brummelkamp TR
[Ad] Endereço:Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands.
[Ti] Título:Genetic wiring maps of single-cell protein states reveal an off-switch for GPCR signalling.
[So] Source:Nature;546(7657):307-311, 2017 06 08.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:As key executers of biological functions, the activity and abundance of proteins are subjected to extensive regulation. Deciphering the genetic architecture underlying this regulation is critical for understanding cellular signalling events and responses to environmental cues. Using random mutagenesis in haploid human cells, we apply a sensitive approach to directly couple genomic mutations to protein measurements in individual cells. Here we use this to examine a suite of cellular processes, such as transcriptional induction, regulation of protein abundance and splicing, signalling cascades (mitogen-activated protein kinase (MAPK), G-protein-coupled receptor (GPCR), protein kinase B (AKT), interferon, and Wingless and Int-related protein (WNT) pathways) and epigenetic modifications (histone crotonylation and methylation). This scalable, sequencing-based procedure elucidates the genetic landscapes that control protein states, identifying genes that cause very narrow phenotypic effects and genes that lead to broad phenotypic consequences. The resulting genetic wiring map identifies the E3-ligase substrate adaptor KCTD5 (ref. 1) as a negative regulator of the AKT pathway, a key signalling cascade frequently deregulated in cancer. KCTD5-deficient cells show elevated levels of phospho-AKT at S473 that could not be attributed to effects on canonical pathway components. To reveal the genetic requirements for this phenotype, we iteratively analysed the regulatory network linked to AKT activity in the knockout background. This genetic modifier screen exposes suppressors of the KCTD5 phenotype and mechanistically demonstrates that KCTD5 acts as an off-switch for GPCR signalling by triggering proteolysis of Gßγ heterodimers dissociated from the Gα subunit. Although biological networks have previously been constructed on the basis of gene expression, protein-protein associations, or genetic interaction profiles, we foresee that the approach described here will enable the generation of a comprehensive genetic wiring map for human cells on the basis of quantitative protein states.
[Mh] Termos MeSH primário: Canais de Potássio/metabolismo
Receptores Acoplados a Proteínas-G/antagonistas & inibidores
Receptores Acoplados a Proteínas-G/metabolismo
Transdução de Sinais/genética
Análise de Célula Única/métodos
[Mh] Termos MeSH secundário: Células Cultivadas
Haploidia
Proteínas Heterotriméricas de Ligação ao GTP/metabolismo
Histonas/química
Histonas/metabolismo
Seres Humanos
Interferons/metabolismo
Proteínas Quinases Ativadas por Mitógeno/metabolismo
Mutagênese
Fenótipo
Fosforilação/genética
Canais de Potássio/deficiência
Canais de Potássio/genética
Proteólise
Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-akt/química
Proteínas Proto-Oncogênicas c-akt/metabolismo
Via de Sinalização Wnt
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Histones); 0 (KCTD5 protein, human); 0 (Potassium Channels); 0 (Receptors, G-Protein-Coupled); 9008-11-1 (Interferons); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 2.7.11.24 (Mitogen-Activated Protein Kinases); EC 3.6.5.1 (Heterotrimeric GTP-Binding Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170601
[St] Status:MEDLINE
[do] DOI:10.1038/nature22376


  7 / 2649 MEDLINE  
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[PMID]:28554852
[Au] Autor:Ke W; Ye D; Mersch K; Xu H; Chen S; Lin F
[Ad] Endereço:Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, USA.
[Ti] Título:Gß1 is required for neutrophil migration in zebrafish.
[So] Source:Dev Biol;428(1):135-147, 2017 08 01.
[Is] ISSN:1095-564X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Signaling mediated by G protein-coupled receptors (GPCRs) is essential for the migration of cells toward chemoattractants. The recruitment of neutrophils to injured tissues in zebrafish larvae is a useful model for studying neutrophil migration and trafficking in vivo. Indeed, the study of this process led to the discovery that PI3Kγ is required for the polarity and motility of neutrophils, features that are necessary for the directed migration of these cells to wounds. However, the mechanism by which PI3Kγ is activated remains to be determined. Here we show that signaling by specifically the heterotrimeric G protein subunit Gß1 is critical for neutrophil migration in response to wounding. In embryos treated with small-molecule inhibitors of Gßγ signaling, neutrophils failed to migrate to wound sites. Although both the Gß1 and Gß4 isoforms are expressed in migrating neutrophils, only deficiency for the former (morpholino-based knockdown) interfered with the directed migration of neutrophils towards wounds. The Gß1 deficiency also impaired the ability of cells to change cell shape and reduced their general motility, defects that are similar to those in neutrophils deficient for PI3Kγ. Transplantation assays showed that the requirement for Gß1 in neutrophil migration is cell autonomous. Finally, live imaging revealed that Gß1 is required for polarized activation of PI3K, and for the actin dynamics that enable neutrophil migration. Collectively, our data indicate that Gß1 signaling controls proper neutrophil migration by activating PI3K and modulating actin dynamics. Moreover, they illustrate a role for a specific Gß isoform in chemotaxis in vivo.
[Mh] Termos MeSH primário: Quimiotaxia de Leucócito/fisiologia
Subunidades beta da Proteína de Ligação ao GTP/metabolismo
Proteínas Heterotriméricas de Ligação ao GTP/metabolismo
Neutrófilos/fisiologia
Cicatrização/fisiologia
Proteínas de Peixe-Zebra/metabolismo
Peixe-Zebra/embriologia
[Mh] Termos MeSH secundário: Animais
Animais Geneticamente Modificados
Classe Ib de Fosfatidilinositol 3-Quinase/metabolismo
Subunidades beta da Proteína de Ligação ao GTP/antagonistas & inibidores
Subunidades beta da Proteína de Ligação ao GTP/genética
Proteínas Heterotriméricas de Ligação ao GTP/antagonistas & inibidores
Proteínas Heterotriméricas de Ligação ao GTP/genética
Morfolinos/genética
Transdução de Sinais
Peixe-Zebra/metabolismo
Proteínas de Peixe-Zebra/antagonistas & inibidores
Proteínas de Peixe-Zebra/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (GNB1 protein, zebrafish); 0 (GTP-Binding Protein beta Subunits); 0 (Morpholinos); 0 (Zebrafish Proteins); EC 2.7.1.137 (Class Ib Phosphatidylinositol 3-Kinase); EC 3.6.5.1 (Heterotrimeric GTP-Binding Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171121
[Lr] Data última revisão:
171121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170531
[St] Status:MEDLINE


  8 / 2649 MEDLINE  
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[PMID]:28489817
[Au] Autor:Flock T; Hauser AS; Lund N; Gloriam DE; Balaji S; Babu MM
[Ad] Endereço:MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
[Ti] Título:Selectivity determinants of GPCR-G-protein binding.
[So] Source:Nature;545(7654):317-322, 2017 05 18.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The selective coupling of G-protein-coupled receptors (GPCRs) to specific G proteins is critical to trigger the appropriate physiological response. However, the determinants of selective binding have remained elusive. Here we reveal the existence of a selectivity barcode (that is, patterns of amino acids) on each of the 16 human G proteins that is recognized by distinct regions on the approximately 800 human receptors. Although universally conserved positions in the barcode allow the receptors to bind and activate G proteins in a similar manner, different receptors recognize the unique positions of the G-protein barcode through distinct residues, like multiple keys (receptors) opening the same lock (G protein) using non-identical cuts. Considering the evolutionary history of GPCRs allows the identification of these selectivity-determining residues. These findings lay the foundation for understanding the molecular basis of coupling selectivity within individual receptors and G proteins.
[Mh] Termos MeSH primário: Proteínas Heterotriméricas de Ligação ao GTP/química
Proteínas Heterotriméricas de Ligação ao GTP/metabolismo
Receptores Acoplados a Proteínas-G/química
Receptores Acoplados a Proteínas-G/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Sítios de Ligação
Evolução Molecular
Seres Humanos
Internet
Modelos Moleculares
Ligação Proteica
Conformação Proteica
Especificidade por Substrato
Interface Usuário-Computador
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Receptors, G-Protein-Coupled); EC 3.6.5.1 (Heterotrimeric GTP-Binding Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170908
[Lr] Data última revisão:
170908
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170511
[St] Status:MEDLINE
[do] DOI:10.1038/nature22070


  9 / 2649 MEDLINE  
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[PMID]:28437792
[Au] Autor:Liang YL; Khoshouei M; Radjainia M; Zhang Y; Glukhova A; Tarrasch J; Thal DM; Furness SGB; Christopoulos G; Coudrat T; Danev R; Baumeister W; Miller LJ; Christopoulos A; Kobilka BK; Wootten D; Skiniotis G; Sexton PM
[Ad] Endereço:Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052 Victoria, Australia.
[Ti] Título:Phase-plate cryo-EM structure of a class B GPCR-G-protein complex.
[So] Source:Nature;546(7656):118-123, 2017 06 01.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, such as osteoporosis, diabetes and obesity. Here we report the structure of a full-length class B receptor, the calcitonin receptor, in complex with peptide ligand and heterotrimeric Gα ßγ protein determined by Volta phase-plate single-particle cryo-electron microscopy. The peptide agonist engages the receptor by binding to an extended hydrophobic pocket facilitated by the large outward movement of the extracellular ends of transmembrane helices 6 and 7. This conformation is accompanied by a 60° kink in helix 6 and a large outward movement of the intracellular end of this helix, opening the bundle to accommodate interactions with the α5-helix of Gα . Also observed is an extended intracellular helix 8 that contributes to both receptor stability and functional G-protein coupling via an interaction with the Gß subunit. This structure provides a new framework for understanding G-protein-coupled receptor function.
[Mh] Termos MeSH primário: Microscopia Crioeletrônica
Proteínas Heterotriméricas de Ligação ao GTP/metabolismo
Proteínas Heterotriméricas de Ligação ao GTP/ultraestrutura
Receptores da Calcitonina/classificação
Receptores da Calcitonina/ultraestrutura
[Mh] Termos MeSH secundário: Sítios de Ligação
Membrana Celular/metabolismo
Sequência Conservada
Proteínas Heterotriméricas de Ligação ao GTP/química
Seres Humanos
Interações Hidrofóbicas e Hidrofílicas
Ligantes
Modelos Moleculares
Conformação Proteica
Receptores da Calcitonina/agonistas
Receptores da Calcitonina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Ligands); 0 (Receptors, Calcitonin); EC 3.6.5.1 (Heterotrimeric GTP-Binding Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170425
[St] Status:MEDLINE
[do] DOI:10.1038/nature22327


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[PMID]:28379944
[Au] Autor:Zhang H; Han GW; Batyuk A; Ishchenko A; White KL; Patel N; Sadybekov A; Zamlynny B; Rudd MT; Hollenstein K; Tolstikova A; White TA; Hunter MS; Weierstall U; Liu W; Babaoglu K; Moore EL; Katz RD; Shipman JM; Garcia-Calvo M; Sharma S; Sheth P; Soisson SM; Stevens RC; Katritch V; Cherezov V
[Ad] Endereço:Department of Chemistry, Bridge Institute, University of Southern California, Los Angeles, California 90089, USA.
[Ti] Título:Structural basis for selectivity and diversity in angiotensin II receptors.
[So] Source:Nature;544(7650):327-332, 2017 04 20.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The angiotensin II receptors AT R and AT R serve as key components of the renin-angiotensin-aldosterone system. AT R has a central role in the regulation of blood pressure, but the function of AT R is unclear and it has a variety of reported effects. To identify the mechanisms that underlie the differences in function and ligand selectivity between these receptors, here we report crystal structures of human AT R bound to an AT R-selective ligand and to an AT R/AT R dual ligand, capturing the receptor in an active-like conformation. Unexpectedly, helix VIII was found in a non-canonical position, stabilizing the active-like state, but at the same time preventing the recruitment of G proteins or ß-arrestins, in agreement with the lack of signalling responses in standard cellular assays. Structure-activity relationship, docking and mutagenesis studies revealed the crucial interactions for ligand binding and selectivity. Our results thus provide insights into the structural basis of the distinct functions of the angiotensin receptors, and may guide the design of new selective ligands.
[Mh] Termos MeSH primário: Modelos Moleculares
Receptor Tipo 2 de Angiotensina/química
Receptor Tipo 2 de Angiotensina/metabolismo
[Mh] Termos MeSH secundário: Bloqueadores do Receptor Tipo 2 de Angiotensina II/química
Bloqueadores do Receptor Tipo 2 de Angiotensina II/metabolismo
Sítios de Ligação/genética
Cristalografia por Raios X
Desenho de Drogas
Proteínas Heterotriméricas de Ligação ao GTP/química
Proteínas Heterotriméricas de Ligação ao GTP/metabolismo
Seres Humanos
Ligantes
Simulação de Acoplamento Molecular
Mutação
Ligação Proteica
Conformação Proteica
Receptor Tipo 1 de Angiotensina/química
Receptor Tipo 1 de Angiotensina/metabolismo
Receptor Tipo 2 de Angiotensina/agonistas
Receptor Tipo 2 de Angiotensina/genética
Transdução de Sinais
Relação Estrutura-Atividade
Especificidade por Substrato/genética
beta-Arrestinas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Angiotensin II Type 2 Receptor Blockers); 0 (Ligands); 0 (Receptor, Angiotensin, Type 1); 0 (Receptor, Angiotensin, Type 2); 0 (beta-Arrestins); EC 3.6.5.1 (Heterotrimeric GTP-Binding Proteins)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170406
[St] Status:MEDLINE
[do] DOI:10.1038/nature22035



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