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[PMID]:28455339
[Au] Autor:Tanaka M; Hiramoto T; Tada H; Shintani T; Gomi K
[Ad] Endereço:Laboratory of Bioindustrial Genomics, Department of Bioindustrial Informatics and Genomics, Graduate School of Agricultural Science, Tohoku University, Aramaki, Aoba-ku, Sendai, Japan.
[Ti] Título:Improved α-Amylase Production by Dephosphorylation Mutation of CreD, an Arrestin-Like Protein Required for Glucose-Induced Endocytosis of Maltose Permease and Carbon Catabolite Derepression in Aspergillus oryzae.
[So] Source:Appl Environ Microbiol;83(13), 2017 Jul 01.
[Is] ISSN:1098-5336
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:produces copious amount of amylolytic enzymes, and MalP, a major maltose permease, is required for the expression of amylase-encoding genes. The expression of these genes is strongly repressed by carbon catabolite repression (CCR) in the presence of glucose. MalP is transported from the plasma membrane to the vacuole by endocytosis, which requires the homolog of E6-AP carboxyl terminus ubiquitin ligase HulA, an ortholog of yeast Rsp5. In yeast, arrestin-like proteins mediate endocytosis as adaptors of Rsp5 and transporters. In the present study, we examined the involvement of CreD, an arrestin-like protein, in glucose-induced MalP endocytosis and CCR of amylase-encoding genes. Deletion of inhibited the glucose-induced endocytosis of MalP, and CreD showed physical interaction with HulA. Phosphorylation of CreD was detected by Western blotting, and two serine residues were determined as the putative phosphorylation sites. However, the phosphorylation state of the serine residues did not regulate MalP endocytosis and its interaction with HulA. Although α-amylase production was significantly repressed by deletion, both phosphorylation and dephosphorylation mimics of CreD had a negligible effect on α-amylase activity. Interestingly, dephosphorylation of CreD was required for CCR relief of amylase genes that was triggered by disruption of the deubiquitinating enzyme-encoding gene The α-amylase activity of the mutant was 1.6-fold higher than that of the wild type, and the dephosphorylation mimic of CreD further improved the α-amylase activity by 2.6-fold. These results indicate that a combination of the dephosphorylation mutation of CreD and disruption increased the production of amylolytic enzymes in In eukaryotes, glucose induces carbon catabolite repression (CCR) and proteolytic degradation of plasma membrane transporters via endocytosis. Glucose-induced endocytosis of transporters is mediated by their ubiquitination, and arrestin-like proteins act as adaptors of transporters and ubiquitin ligases. In this study, we showed that CreD, an arrestin-like protein, is involved in glucose-induced endocytosis of maltose permease and carbon catabolite derepression of amylase gene expression in Dephosphorylation of CreD was required for CCR relief triggered by the disruption of , which encodes a deubiquitinating enzyme; a combination of the phosphorylation-defective mutation of CreD and disruption dramatically improved α-amylase production. This study shows the dual function of an arrestin-like protein and provides a novel approach for improving the production of amylolytic enzymes in .
[Mh] Termos MeSH primário: Arrestina/metabolismo
Aspergillus oryzae/metabolismo
Repressão Catabólica
Endocitose
Proteínas Fúngicas/genética
Proteínas de Transporte de Monossacarídeos/genética
alfa-Amilases/genética
[Mh] Termos MeSH secundário: Arrestina/genética
Aspergillus oryzae/enzimologia
Aspergillus oryzae/genética
Carbono/metabolismo
Proteínas Fúngicas/metabolismo
Regulação Fúngica da Expressão Gênica
Glucose/metabolismo
Proteínas de Transporte de Monossacarídeos/metabolismo
Mutação
Fosforilação
Transporte Proteico
alfa-Amilases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Arrestin); 0 (Fungal Proteins); 0 (Monosaccharide Transport Proteins); 7440-44-0 (Carbon); 9055-23-6 (maltose permease); EC 3.2.1.1 (alpha-Amylases); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171225
[Lr] Data última revisão:
171225
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE


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[PMID]:28468835
[Au] Autor:Hovsepian J; Defenouillère Q; Albanèse V; Váchová L; Garcia C; Palková Z; Léon S
[Ad] Endereço:Institut Jacques Monod, UMR 7592 Centre National de la Recherche Scientifique/Université Paris-Diderot, Sorbonne Paris Cité, 75013 Paris, France.
[Ti] Título:Multilevel regulation of an α-arrestin by glucose depletion controls hexose transporter endocytosis.
[So] Source:J Cell Biol;216(6):1811-1831, 2017 Jun 05.
[Is] ISSN:1540-8140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nutrient availability controls the landscape of nutrient transporters present at the plasma membrane, notably by regulating their ubiquitylation and subsequent endocytosis. In yeast, this involves the Nedd4 ubiquitin ligase Rsp5 and arrestin-related trafficking adaptors (ARTs). ARTs are targeted by signaling pathways and warrant that cargo ubiquitylation and endocytosis appropriately respond to nutritional inputs. Here, we show that glucose deprivation regulates the ART protein Csr2/Art8 at multiple levels to trigger high-affinity glucose transporter endocytosis. Csr2 is transcriptionally induced in these conditions through the AMPK orthologue Snf1 and downstream transcriptional repressors. Upon synthesis, Csr2 becomes activated by ubiquitylation. In contrast, glucose replenishment induces transcriptional shutdown and switches Csr2 to an inactive, deubiquitylated form. This glucose-induced deubiquitylation of Csr2 correlates with its phospho-dependent association with 14-3-3 proteins and involves protein kinase A. Thus, two glucose signaling pathways converge onto Csr2 to regulate hexose transporter endocytosis by glucose availability. These data illustrate novel mechanisms by which nutrients modulate ART activity and endocytosis.
[Mh] Termos MeSH primário: Arrestina/metabolismo
Endocitose
Glucose/deficiência
Proteínas de Transporte de Monossacarídeos/metabolismo
Proteínas Nucleares/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
Saccharomyces cerevisiae/metabolismo
[Mh] Termos MeSH secundário: Proteínas 14-3-3/metabolismo
Arrestina/genética
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo
Regulação Fúngica da Expressão Gênica
Proteínas de Transporte de Monossacarídeos/genética
Mutação
Proteínas Nucleares/genética
Proteína Fosfatase 1/metabolismo
Proteínas Serina-Treonina Quinases/metabolismo
Proteínas Repressoras/metabolismo
Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/genética
Fatores de Tempo
Transcrição Genética
Ubiquitinação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (14-3-3 Proteins); 0 (Arrestin); 0 (BMH1 protein, S cerevisiae); 0 (BMH2 protein, S cerevisiae); 0 (Csr2 protein, S cerevisiae); 0 (HXT7 protein, S cerevisiae); 0 (Hxt6 protein, S cerevisiae); 0 (MIG1 protein, S cerevisiae); 0 (Mig2 protein, S cerevisiae); 0 (Monosaccharide Transport Proteins); 0 (Nuclear Proteins); 0 (Repressor Proteins); 0 (Saccharomyces cerevisiae Proteins); EC 2.7.1.- (SNF1-related protein kinases); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases); EC 3.1.3.16 (Protein Phosphatase 1); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171205
[Lr] Data última revisão:
171205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1083/jcb.201610094


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[PMID]:28549094
[Au] Autor:Sullivan LS; Bowne SJ; Koboldt DC; Cadena EL; Heckenlively JR; Branham KE; Wheaton DH; Jones KD; Ruiz RS; Pennesi ME; Yang P; Davis-Boozer D; Northrup H; Gurevich VV; Chen R; Xu M; Li Y; Birch DG; Daiger SP
[Ad] Endereço:Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston, Texas, United States.
[Ti] Título:A Novel Dominant Mutation in SAG, the Arrestin-1 Gene, Is a Common Cause of Retinitis Pigmentosa in Hispanic Families in the Southwestern United States.
[So] Source:Invest Ophthalmol Vis Sci;58(5):2774-2784, 2017 May 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: To identify the causes of autosomal dominant retinitis pigmentosa (adRP) in a cohort of families without mutations in known adRP genes and consequently to characterize a novel dominant-acting missense mutation in SAG. Methods: Patients underwent ophthalmologic testing and were screened for mutations using targeted-capture and whole-exome next-generation sequencing. Confirmation and additional screening were done by Sanger sequencing. Haplotypes segregating with the mutation were determined using short tandem repeat and single nucleotide variant polymorphisms. Genealogies were established by interviews of family members. Results: Eight families in a cohort of 300 adRP families, and four additional families, were found to have a novel heterozygous mutation in the SAG gene, c.440G>T; p.Cys147Phe. Patients exhibited symptoms of retinitis pigmentosa and none showed symptoms characteristic of Oguchi disease. All families are of Hispanic descent and most were ascertained in Texas or California. A single haplotype including the SAG mutation was identified in all families. The mutation dramatically alters a conserved amino acid, is extremely rare in global databases, and was not found in 4000+ exomes from Hispanic controls. Molecular modeling based on the crystal structure of bovine arrestin-1 predicts protein misfolding/instability. Conclusions: This is the first dominant-acting mutation identified in SAG, a founder mutation possibly originating in Mexico several centuries ago. The phenotype is clearly adRP and is distinct from the previously reported phenotypes of recessive null mutations, that is, Oguchi disease and recessive RP. The mutation accounts for 3% of the 300 families in the adRP Cohort and 36% of Hispanic families in this cohort.
[Mh] Termos MeSH primário: Arrestina/genética
Genes Dominantes
Hispano-Americanos/genética
Mutação de Sentido Incorreto
Retinite Pigmentosa/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Análise Mutacional de DNA
Éxons/genética
Feminino
Sequenciamento de Nucleotídeos em Larga Escala
Seres Humanos
Masculino
Meia-Idade
Linhagem
Retina/fisiopatologia
Retinite Pigmentosa/diagnóstico
Retinite Pigmentosa/fisiopatologia
Sudoeste dos Estados Unidos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Arrestin)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170717
[Lr] Data última revisão:
170717
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170527
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.16-21341


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[PMID]:28129538
[Au] Autor:Wacker D; Wang S; McCorvy JD; Betz RM; Venkatakrishnan AJ; Levit A; Lansu K; Schools ZL; Che T; Nichols DE; Shoichet BK; Dror RO; Roth BL
[Ad] Endereço:Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599-7365, USA. Electronic address: dwacker@email.unc.edu.
[Ti] Título:Crystal Structure of an LSD-Bound Human Serotonin Receptor.
[So] Source:Cell;168(3):377-389.e12, 2017 Jan 26.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The prototypical hallucinogen LSD acts via serotonin receptors, and here we describe the crystal structure of LSD in complex with the human serotonin receptor 5-HT . The complex reveals conformational rearrangements to accommodate LSD, providing a structural explanation for the conformational selectivity of LSD's key diethylamide moiety. LSD dissociates exceptionally slow from both 5-HT R and 5-HT R-a major target for its psychoactivity. Molecular dynamics (MD) simulations suggest that LSD's slow binding kinetics may be due to a "lid" formed by extracellular loop 2 (EL2) at the entrance to the binding pocket. A mutation predicted to increase the mobility of this lid greatly accelerates LSD's binding kinetics and selectively dampens LSD-mediated ß-arrestin2 recruitment. This study thus reveals an unexpected binding mode of LSD; illuminates key features of its kinetics, stereochemistry, and signaling; and provides a molecular explanation for LSD's actions at human serotonin receptors. PAPERCLIP.
[Mh] Termos MeSH primário: Dietilamida do Ácido Lisérgico/química
Receptor 5-HT2B de Serotonina/química
[Mh] Termos MeSH secundário: Arrestina/química
Cristalografia por Raios X
Seres Humanos
Cinética
Modelos Químicos
Simulação de Dinâmica Molecular
[Pt] Tipo de publicação:JOURNAL ARTICLE; COMMENT
[Nm] Nome de substância:
0 (Arrestin); 0 (Receptor, Serotonin, 5-HT2B); 8NA5SWF92O (Lysergic Acid Diethylamide)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170128
[St] Status:MEDLINE


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[PMID]:27927913
[Au] Autor:Dhopeshwarkar A; Murataeva N; Makriyannis A; Straiker A; Mackie K
[Ad] Endereço:Department of Psychological and Brain Sciences, Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana (A.D., N.M., A.S., K.M.); and Department of Pharmaceutical Sciences, Center for Drug Discovery, Northeastern University, Boston, Massachusetts (A.M.).
[Ti] Título:Two Janus Cannabinoids That Are Both CB2 Agonists and CB1 Antagonists.
[So] Source:J Pharmacol Exp Ther;360(2):300-311, 2017 Feb.
[Is] ISSN:1521-0103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The cannabinoid signaling system includes two G protein-coupled receptors, CB and CB These receptors are widely distributed throughout the body and have each been implicated in many physiologically important processes. Although the cannabinoid signaling system has therapeutic potential, the development of receptor-selective ligands remains a persistent hurdle. Because CB and CB are involved in diverse processes, it would be advantageous to develop ligands that differentially engage CB and CB We now report that GW405833 [1-(2,3-dichlorobenzoyl)-5-methoxy-2-methyl-3-[2-(4-morpholinyl)ethyl]-1H-indole] and AM1710 [1-hydroxy-9-methoxy-3-(2-methyloctan-2-yl)benzo[c]chromen-6-one], described as selective CB agonists, can antagonize CB receptor signaling. In autaptic hippocampal neurons, GW405833 and AM1710 both interfered with CB -mediated depolarization-induced suppression of excitation, with GW405833 being more potent. In addition, in CB -expressing human embryonic kidney 293 cells, GW405833 noncompetitively antagonized adenylyl cyclase activity, extracellular signal-regulated kinase 1/2 phosphorylation, phosphatidylinositol 4,5-bisphosphate signaling, and CB internalization by CP55940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol). In contrast, AM1710 behaved as a low-potency competitive antagonist/inverse agonist in these signaling pathways. GW405833 interactions with CB /arrestin signaling were complex: GW405833 differentially modulated arrestin recruitment in a time-dependent fashion, with an initial modest potentiation at 20 minutes followed by antagonism starting at 1 hour. AM1710 acted as a low-efficacy agonist in arrestin signaling at the CB receptor, with no evident time dependence. In summary, we determined that GW405833 and AM1710 are not only CB agonists but also CB antagonists, with distinctive and complex signaling properties. Thus, experiments using these compounds must take into account their potential activity at CB receptors.
[Mh] Termos MeSH primário: Cromonas/farmacologia
Indóis/farmacologia
Morfolinas/farmacologia
Receptor CB1 de Canabinoide/antagonistas & inibidores
Receptor CB2 de Canabinoide/agonistas
[Mh] Termos MeSH secundário: Animais
Arrestina/metabolismo
Colforsina/farmacologia
AMP Cíclico/metabolismo
Relação Dose-Resposta a Droga
Ativação Enzimática/efeitos dos fármacos
Células HEK293
Hipocampo/citologia
Seres Humanos
Fosfatos de Inositol/metabolismo
Camundongos
Proteína Quinase 1 Ativada por Mitógeno/metabolismo
Proteína Quinase 3 Ativada por Mitógeno/metabolismo
Neurônios/citologia
Neurônios/efeitos dos fármacos
Fosfoproteínas/metabolismo
Transporte Proteico/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1-(2,3-dichlorobenzoyl)-5-methoxy-2-methyl-(2-(mopholin-4-yl)ethyl)-1H-indole); 0 (3-(1,1-dimethyl-heptyl)-1-hydroxy-9-methoxy-benzo(c)chromen-6-one); 0 (Arrestin); 0 (Chromones); 0 (Indoles); 0 (Inositol Phosphates); 0 (Morpholines); 0 (Phosphoproteins); 0 (Receptor, Cannabinoid, CB1); 0 (Receptor, Cannabinoid, CB2); 1F7A44V6OU (Colforsin); E0399OZS9N (Cyclic AMP); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170516
[Lr] Data última revisão:
170516
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161209
[St] Status:MEDLINE
[do] DOI:10.1124/jpet.116.236539


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[PMID]:27757763
[Au] Autor:Hudson BD
[Ad] Endereço:Centre for Translational Pharmacology, Institute of Molecular, Cell and Systems Biology, University of Glasgow, Glasgow, G12 8QQ, UK. Brian.Hudson@Glasgow.ac.uk.
[Ti] Título:Using Biosensors to Study Free Fatty Acid Receptor Pharmacology and Function.
[So] Source:Handb Exp Pharmacol;236:79-100, 2017.
[Is] ISSN:0171-2004
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The free fatty acid (FFA) family of G protein coupled receptors (GPCRs) has generated significant interest for exploiting its members as potential drug targets. However, unravelling the complex pharmacology of this family of receptors has proven challenging. In recent years the use of biosensor technologies capable of assessing biological functions in living cells, and in real time, has greatly enhanced our ability to study GPCR pharmacology and function. These include genetically encoded sensors that change the intensity or wavelength of light emitted from a bioluminescent or fluorescent protein in response to a stimulus, as well as non-genetically encoded sensors able to measure more global cellular changes, such as mass redistribution within a cell. This chapter will examine how these sensors can be used to study GPCRs, and in particular how they are helping uncover the pharmacology of the FFA family of receptors.
[Mh] Termos MeSH primário: Técnicas Biossensoriais/métodos
Ácidos Graxos não Esterificados/metabolismo
Receptores Acoplados a Proteínas-G/fisiologia
[Mh] Termos MeSH secundário: Animais
Arrestina/análise
Seres Humanos
Receptores Acoplados a Proteínas-G/efeitos dos fármacos
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Arrestin); 0 (Fatty Acids, Nonesterified); 0 (Receptors, G-Protein-Coupled)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161021
[St] Status:MEDLINE
[do] DOI:10.1007/164_2016_58


  7 / 1255 MEDLINE  
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[PMID]:27839952
[Au] Autor:Eddy MT; Didenko T; Stevens RC; Wüthrich K
[Ad] Endereço:Departments of Biological Sciences and Chemistry, Bridge Institute, The University of Southern California, South Vermont Avenue, MC 3303, Los Angeles, CA 90089, USA.
[Ti] Título:ß -Adrenergic Receptor Conformational Response to Fusion Protein in the Third Intracellular Loop.
[So] Source:Structure;24(12):2190-2197, 2016 Dec 06.
[Is] ISSN:1878-4186
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fluorine-19 nuclear magnetic resonance (NMR) was used to study conformational equilibria at the intracellular tips of helices VI and VII in a variant ß -adrenergic receptor (ß AR) containing T4-lysozyme fused into the third intracellular loop (ß AR-T4L), a G protein-coupled receptor (GPCR) modification widely used in crystal structure determination. G-protein signaling at helix VI showed nearly complete population of an active-like state for all ligand efficacies in the absence of an intracellular protein. For arrestin signaling at helix VII, a native-like equilibrium was observed, except for complexes with ligands devoid of a hydrophobic moiety at the ethanolamine end. These data confirm that response of G-protein and arrestin signaling to ligand efficacy is not coupled, and presents evidence for long-range effects between fusion protein and orthosteric binding cavity, which are suppressed by voluminous bound ligands. Solution NMR thus provides complementary information, which should be considered in functional interpretations of GPCR crystal structures obtained with ICL3 fusions.
[Mh] Termos MeSH primário: Arrestina/metabolismo
Muramidase/metabolismo
Receptores Adrenérgicos beta 2/química
Receptores Adrenérgicos beta 2/metabolismo
[Mh] Termos MeSH secundário: Sítios de Ligação
Cristalografia por Raios X
Seres Humanos
Modelos Moleculares
Ressonância Magnética Nuclear Biomolecular
Estrutura Secundária de Proteína
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Arrestin); 0 (Receptors, Adrenergic, beta-2); EC 3.2.1.17 (Muramidase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170628
[Lr] Data última revisão:
170628
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161115
[St] Status:MEDLINE


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[PMID]:27798240
[Au] Autor:Guiney EL; Klecker T; Emr SD
[Ad] Endereço:Weill Institute for Cell and Molecular Biology and Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853.
[Ti] Título:Identification of the endocytic sorting signal recognized by the Art1-Rsp5 ubiquitin ligase complex.
[So] Source:Mol Biol Cell;27(25):4043-4054, 2016 Dec 15.
[Is] ISSN:1939-4586
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Targeted endocytosis of plasma membrane (PM) proteins allows cells to adjust their complement of membrane proteins to changing extracellular conditions. For a wide variety of PM proteins, initiation of endocytosis is triggered by ubiquitination. In yeast, arrestin-related trafficking adaptors (ARTs) enable a single ubiquitin ligase, Rsp5, to specifically and selectively target a wide range of PM proteins for ubiquitination and endocytosis. However, the mechanisms that allow ARTs to specifically recognize their appropriate substrates are unknown. We present the molecular features in the methionine permease Mup1 that are required for Art1-Rsp5-mediated ubiquitination and endocytosis. A combination of genetics, fluorescence microscopy, and biochemistry reveals three critical features that comprise an ART sorting signal in the Mup1 N-terminal cytosolic tail: 1) an extended acidic patch, 2) in close proximity to the first Mup1 transmembrane domain, and 3) close to the ubiquitinated lysines. We show that a functionally similar ART sorting signal is also required for the endocytosis of a second Art1-dependent cargo, Can1, suggesting a common mechanism for recognition of Art1 substrates. We isolate two separate suppressor mutations in the Art1 C-terminal domain that allele-specifically restore endocytosis of two Mup1 acidic patch mutants, consistent with an interaction between the Art1 C-terminus and the Mup1 acidic patch. We propose that this interaction is required for recruitment of the Art1-Rsp5 ubiquitination complex.
[Mh] Termos MeSH primário: Proteínas de Ligação a DNA/metabolismo
Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo
Proteínas/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
Fatores de Transcrição/metabolismo
Complexos Ubiquitina-Proteína Ligase/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Arrestina/metabolismo
Citoplasma/metabolismo
Citosol/metabolismo
Endocitose
Proteínas de Membrana Transportadoras/metabolismo
Sinais Direcionadores de Proteínas
Proteínas/genética
Saccharomyces cerevisiae/enzimologia
Saccharomyces cerevisiae/metabolismo
Ubiquitina/metabolismo
Ubiquitinação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Arrestin); 0 (DNA-Binding Proteins); 0 (Endosomal Sorting Complexes Required for Transport); 0 (Membrane Transport Proteins); 0 (Protein Sorting Signals); 0 (Proteins); 0 (SWI4 protein, S cerevisiae); 0 (Saccharomyces cerevisiae Proteins); 0 (Transcription Factors); 0 (Ubiquitin); 0 (major urinary proteins); EC 2.3.2.23 (Ubiquitin-Protein Ligase Complexes); EC 6.3.2.- (RSP5 protein, S cerevisiae)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161101
[St] Status:MEDLINE


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[PMID]:27348044
[Au] Autor:Yang J; Shen Z; Jiang X; Yang H; Huang H; Jin L; Chen Y; Shi L; Zhou N
[Ad] Endereço:National Engineering Research Center of Marine Facilities Aquaculture, Zhejiang Ocean University , Zhoushan, Zhejiang 316022, China.
[Ti] Título:Agonist-Activated Bombyx Corazonin Receptor Is Internalized via an Arrestin-Dependent and Clathrin-Independent Pathway.
[So] Source:Biochemistry;55(28):3874-87, 2016 Jul 19.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Agonist-induced internalization plays a key role in the tight regulation of the extent and duration of G protein-coupled receptor signaling. Previously, we have shown that the Bombyx corazonin receptor (BmCrzR) activates both Gαq- and Gαs-dependent signaling cascades. However, the molecular mechanisms involved in the regulation of the internalization and desensitization of BmCrzR remain to be elucidated. Here, vectors for expressing BmCrzR fused with enhanced green fluorescent protein (EGFP) at the C-terminal end were used to further characterize BmCrzR internalization. We found that the BmCrzR heterologously expressed in HEK-293 and BmN cells was rapidly internalized from the plasma membrane into the cytoplasm in a concentration- and time-dependent manner via a ß-arrestin (Kurtz)-dependent and clathrin-independent pathway in response to agonist challenge. While most of the internalized receptors were recycled to the cell surface via early endosomes, some others were transported to lysosomes for degradation. Assays using RNA interference revealed that both GRK2 and GRK5 were essentially involved in the regulation of BmCrzR phosphorylation and internalization. Further investigations indicated that the identified cluster of Ser/Thr residues ((411)TSS(413)) was responsible for GRK-mediated phosphorylation and internalization. This is the first detailed investigation of the internalization and trafficking of Bombyx corazonin receptors.
[Mh] Termos MeSH primário: Arrestina/metabolismo
Bombyx/metabolismo
Clatrina/metabolismo
Receptores de Neuropeptídeos/agonistas
Receptores de Neuropeptídeos/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Membrana Celular/metabolismo
Dinaminas/metabolismo
Quinase 2 de Receptor Acoplado a Proteína G/metabolismo
Quinase 5 de Receptor Acoplado a Proteína G/metabolismo
Células HEK293
Seres Humanos
Lisossomos/metabolismo
Transporte Proteico
Receptores de Neuropeptídeos/química
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Arrestin); 0 (Clathrin); 0 (Receptors, Neuropeptide); 0 (corazonin receptor); EC 2.7.11.15 (ADRBK1 protein, human); EC 2.7.11.16 (G-Protein-Coupled Receptor Kinase 2); EC 2.7.11.16 (G-Protein-Coupled Receptor Kinase 5); EC 2.7.11.16 (GRK5 protein, human); EC 3.6.5.5 (Dynamins)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170501
[Lr] Data última revisão:
170501
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160628
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.6b00250


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[PMID]:27313176
[Au] Autor:Nasri I; Bonnet D; Zwarycz B; d'Aldebert E; Khou S; Mezghani-Jarraya R; Quaranta M; Rolland C; Bonnart C; Mas E; Ferrand A; Cenac N; Magness S; Van Landeghem L; Vergnolle N; Racaud-Sultan C
[Ad] Endereço:Institut de Recherche en Santé Digestive, Université de Toulouse, Institut National de la Santé et de la Recherche Médicale, Institut National de la Recherche Agronomique, Ecole Nationale Vétérinaire de Toulouse, Université Paul Sabatier, Toulouse, France; Laboratoire de Chimie des Substances Nature
[Ti] Título:PAR2-dependent activation of GSK3ß regulates the survival of colon stem/progenitor cells.
[So] Source:Am J Physiol Gastrointest Liver Physiol;311(2):G221-36, 2016 Aug 01.
[Is] ISSN:1522-1547
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Protease-activated receptors PAR1 and PAR2 play an important role in the control of epithelial cell proliferation and migration. However, the survival of normal and tumor intestinal stem/progenitor cells promoted by proinflammatory mediators may be critical in oncogenesis. The glycogen synthase kinase-3ß (GSK3ß) pathway is overactivated in colon cancer cells and promotes their survival and drug resistance. We thus aimed to determine PAR1 and PAR2 effects on normal and tumor intestinal stem/progenitor cells and whether they involved GSK3ß. First, PAR1 and PAR2 were identified in colon stem/progenitor cells by immunofluorescence. In three-dimensional cultures of murine crypt units or single tumor Caco-2 cells, PAR2 activation decreased numbers and size of normal or cancerous spheroids, and PAR2-deficient spheroids showed increased proliferation, indicating that PAR2 represses proliferation. PAR2-stimulated normal cells were more resistant to stress (serum starvation or spheroid passaging), suggesting prosurvival effects of PAR2 Accordingly, active caspase-3 was strongly increased in PAR2-deficient normal spheroids. PAR2 but not PAR1 triggered GSK3ß activation through serine-9 dephosphorylation in normal and tumor cells. The PAR2-triggered GSK3ß activation implicates an arrestin/PP2A/GSK3ß complex that is dependent on the Rho kinase activity. Loss of PAR2 was associated with high levels of GSK3ß nonactive form, strengthening the role of PAR2 in GSK3ß activation. GSK3 pharmacological inhibition impaired the survival of PAR2-stimulated spheroids and serum-starved cells. Altogether our data identify PAR2/GSK3ß as a novel pathway that plays a critical role in the regulation of stem/progenitor cell survival and proliferation in normal colon crypts and colon cancer.
[Mh] Termos MeSH primário: Colo/enzimologia
Células Epiteliais/enzimologia
Glicogênio Sintase Quinase 3 beta/metabolismo
Células-Tronco Neoplásicas/enzimologia
Receptor PAR-2/metabolismo
Células-Tronco/enzimologia
[Mh] Termos MeSH secundário: Animais
Arrestina/metabolismo
Células CACO-2
Proliferação Celular
Sobrevivência Celular
Colo/patologia
Ativação Enzimática
Células Epiteliais/patologia
Seres Humanos
Masculino
Camundongos Endogâmicos C57BL
Células-Tronco Neoplásicas/patologia
Fosforilação
Proteína Fosfatase 2/metabolismo
Interferência de RNA
Receptor PAR-2/genética
Transdução de Sinais
Esferoides Celulares
Nicho de Células-Tronco
Células-Tronco/patologia
Transfecção
Microambiente Tumoral
Quinases Associadas a rho/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Arrestin); 0 (Receptor, PAR-2); EC 2.7.11.1 (GSK3B protein, human); EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta); EC 2.7.11.1 (Gsk3b protein, mouse); EC 2.7.11.1 (rho-Associated Kinases); EC 3.1.3.16 (Protein Phosphatase 2)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170801
[Lr] Data última revisão:
170801
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160618
[St] Status:MEDLINE
[do] DOI:10.1152/ajpgi.00328.2015



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