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  1 / 12711 MEDLINE  
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[PMID]:29236391
[Au] Autor:Suleimanova RR; Hudz EA; Melnychuk DO; Kalachniuk LH
[Ti] Título:Age-related changes phospholipids of sterlet in liver and dorsal muscles.
[So] Source:Ukr Biochem J;89(1):71-5, 2017 Jan-Feb.
[Is] ISSN:2409-4943
[Cp] País de publicação:Ukraine
[La] Idioma:eng
[Ab] Resumo:Study of phospholipids changes peculiarities in the liver and dorsal muscles of sterlet (Acipenser ruthenus Linnaeus) may be important to determine the etiology and pathogenesis of fatty liver. We established that the content of total phospholipids in tissues of the liver and dorsal muscles of three-year-old sterlet was less than for two-year-old fish by 15% and 20% (P ≤ 0.01), respectively. The amount of phosphatidylcholine (P ≤ 0.05), phosphatidylethanolamine, phosphatidylserine (P ≤ 0.01), phosphatidylinositol (P ≤ 0.01) and cardiolipin in the liver of 3-year-old sterlet was lower than for the 2-year-old fish, while quantitative indices for lysophosphatidylcholine and sphingomyelin were slightly increased. Similarly, in the cells of the dorsal muscles, the amount of phospholipid components (except lysophosphatidylcholine) was decreased with age. A decrease in the amount of phosphatidylethanolamine and phosphatidylserine in the dorsal muscles of 3-year-old sterlet was significant. The major phospholipids respective distribution was stable, except for phosphatidylethanolamine and particularly sphingomyelin.
[Mh] Termos MeSH primário: Envelhecimento/metabolismo
Fígado/metabolismo
Músculos/metabolismo
Fosfolipídeos/metabolismo
[Mh] Termos MeSH secundário: Animais
Cardiolipinas/metabolismo
Peixes
Fígado/química
Lisofosfatidilcolinas/metabolismo
Músculos/química
Fosfatidilcolinas/metabolismo
Fosfatidiletanolaminas/metabolismo
Fosfatidilinositóis/metabolismo
Fosfatidilserinas/metabolismo
Esfingomielinas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cardiolipins); 0 (Lysophosphatidylcholines); 0 (Phosphatidylcholines); 0 (Phosphatidylethanolamines); 0 (Phosphatidylinositols); 0 (Phosphatidylserines); 0 (Phospholipids); 0 (Sphingomyelins); 39382-08-6 (phosphatidylethanolamine)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171214
[St] Status:MEDLINE
[do] DOI:10.15407/ubj89.01.071


  2 / 12711 MEDLINE  
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[PMID]:28969385
[Au] Autor:Alcantara D; Timms AE; Gripp K; Baker L; Park K; Collins S; Cheng C; Stewart F; Mehta SG; Saggar A; Sztriha L; Zombor M; Caluseriu O; Mesterman R; Van Allen MI; Jacquinet A; Ygberg S; Bernstein JA; Wenger AM; Guturu H; Bejerano G; Gomez-Ospina N; Lehman A; Alfei E; Pantaleoni C; Conti V; Guerrini R; Moog U; Graham JM; Hevner R; Dobyns WB; O'Driscoll M; Mirzaa GM
[Ad] Endereço:Genome Damage and Stability Centre, University of Sussex, Sussex, UK.
[Ti] Título:Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly.
[So] Source:Brain;140(10):2610-2622, 2017 Oct 01.
[Is] ISSN:1460-2156
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as hemimegalencephaly, focal cortical dysplasia and polymicrogyria). Mutations of the AKT3 gene have been reported in a few individuals with brain malformations, to date. Therefore, our understanding regarding the clinical and molecular spectrum associated with mutations of this critical gene is limited, with no clear genotype-phenotype correlations. We sought to further delineate this spectrum, study levels of mosaicism and identify genotype-phenotype correlations of AKT3-related disorders. We performed targeted sequencing of AKT3 on individuals with these phenotypes by molecular inversion probes and/or Sanger sequencing to determine the type and level of mosaicism of mutations. We analysed all clinical and brain imaging data of mutation-positive individuals including neuropathological analysis in one instance. We performed ex vivo kinase assays on AKT3 engineered with the patient mutations and examined the phospholipid binding profile of pleckstrin homology domain localizing mutations. We identified 14 new individuals with AKT3 mutations with several phenotypes dependent on the type of mutation and level of mosaicism. Our comprehensive clinical characterization, and review of all previously published patients, broadly segregates individuals with AKT3 mutations into two groups: patients with highly asymmetric cortical dysplasia caused by the common p.E17K mutation, and patients with constitutional AKT3 mutations exhibiting more variable phenotypes including bilateral cortical malformations, polymicrogyria, periventricular nodular heterotopia and diffuse megalencephaly without cortical dysplasia. All mutations increased kinase activity, and pleckstrin homology domain mutants exhibited enhanced phospholipid binding. Overall, our study shows that activating mutations of the critical AKT3 gene are associated with a wide spectrum of brain involvement ranging from focal or segmental brain malformations (such as hemimegalencephaly and polymicrogyria) predominantly due to mosaic AKT3 mutations, to diffuse bilateral cortical malformations, megalencephaly and heterotopia due to constitutional AKT3 mutations. We also provide the first detailed neuropathological examination of a child with extreme megalencephaly due to a constitutional AKT3 mutation. This child has one of the largest documented paediatric brain sizes, to our knowledge. Finally, our data show that constitutional AKT3 mutations are associated with megalencephaly, with or without autism, similar to PTEN-related disorders. Recognition of this broad clinical and molecular spectrum of AKT3 mutations is important for providing early diagnosis and appropriate management of affected individuals, and will facilitate targeted design of future human clinical trials using PI3K-AKT pathway inhibitors.
[Mh] Termos MeSH primário: Deficiências do Desenvolvimento/genética
Megalencefalia/genética
Mutação/genética
Proteínas Proto-Oncogênicas c-akt/genética
[Mh] Termos MeSH secundário: Encéfalo/diagnóstico por imagem
Criança
Deficiências do Desenvolvimento/diagnóstico por imagem
Deficiências do Desenvolvimento/patologia
Feminino
Estudos de Associação Genética
Células HEK293
Seres Humanos
Imunoprecipitação
Imagem por Ressonância Magnética
Masculino
Megalencefalia/diagnóstico por imagem
Megalencefalia/patologia
Mutagênese Sítio-Dirigida/métodos
Fosfatidilinositóis/metabolismo
Transfecção
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Phosphatidylinositols); EC 2.7.11.1 (AKT3 protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171004
[St] Status:MEDLINE
[do] DOI:10.1093/brain/awx203


  3 / 12711 MEDLINE  
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[PMID]:28928133
[Au] Autor:Casanova JE; Winckler B
[Ad] Endereço:Department of Cell Biology, University of Virginia, Charlottesville, VA.
[Ti] Título:A new Rab7 effector controls phosphoinositide conversion in endosome maturation.
[So] Source:J Cell Biol;216(10):2995-2997, 2017 Oct 02.
[Is] ISSN:1540-8140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Endosome maturation requires a coordinated change in the Rab GTPase and phosphoinositide composition of the endosomal membrane. In this issue, Liu et al. (2017. https://doi.org/10.1083/jcb.201705151) identify WDR91 as a ubiquitous Rab7 effector that inhibits phosphatidylinositol 3-kinase activity on endosomes and is critical for endosome maturation, viability, and dendrite growth of neurons in vivo.
[Mh] Termos MeSH primário: Endossomos
Proteínas rab de Ligação ao GTP
[Mh] Termos MeSH secundário: Fosfatidilinositol 3-Quinases
Fosfatidilinositóis
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Phosphatidylinositols); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 3.6.5.2 (rab GTP-Binding Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170921
[St] Status:MEDLINE
[do] DOI:10.1083/jcb.201709034


  4 / 12711 MEDLINE  
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[PMID]:28872463
[Au] Autor:Bartolomeo R; Cinque L; De Leonibus C; Forrester A; Salzano AC; Monfregola J; De Gennaro E; Nusco E; Azario I; Lanzara C; Serafini M; Levine B; Ballabio A; Settembre C
[Ad] Endereço:Telethon Institute of Genetics and Medicine (TIGEM), and.
[Ti] Título:mTORC1 hyperactivation arrests bone growth in lysosomal storage disorders by suppressing autophagy.
[So] Source:J Clin Invest;127(10):3717-3729, 2017 Oct 02.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The mammalian target of rapamycin complex 1 (mTORC1) kinase promotes cell growth by activating biosynthetic pathways and suppressing catabolic pathways, particularly that of macroautophagy. A prerequisite for mTORC1 activation is its translocation to the lysosomal surface. Deregulation of mTORC1 has been associated with the pathogenesis of several diseases, but its role in skeletal disorders is largely unknown. Here, we show that enhanced mTORC1 signaling arrests bone growth in lysosomal storage disorders (LSDs). We found that lysosomal dysfunction induces a constitutive lysosomal association and consequent activation of mTORC1 in chondrocytes, the cells devoted to bone elongation. mTORC1 hyperphosphorylates the protein UV radiation resistance-associated gene (UVRAG), reducing the activity of the associated Beclin 1-Vps34 complex and thereby inhibiting phosphoinositide production. Limiting phosphoinositide production leads to a blockage of the autophagy flux in LSD chondrocytes. As a consequence, LSD chondrocytes fail to properly secrete collagens, the main components of the cartilage extracellular matrix. In mouse models of LSD, normalization of mTORC1 signaling or stimulation of the Beclin 1-Vps34-UVRAG complex rescued the autophagy flux, restored collagen levels in cartilage, and ameliorated the bone phenotype. Taken together, these data unveil a role for mTORC1 and autophagy in the pathogenesis of skeletal disorders and suggest potential therapeutic approaches for the treatment of LSDs.
[Mh] Termos MeSH primário: Autofagia
Desenvolvimento Ósseo
Doenças por Armazenamento dos Lisossomos/metabolismo
Complexos Multiproteicos/metabolismo
Serina-Treonina Quinases TOR/metabolismo
[Mh] Termos MeSH secundário: Animais
Beclina-1/genética
Beclina-1/metabolismo
Condrócitos/metabolismo
Condrócitos/patologia
Doenças por Armazenamento dos Lisossomos/genética
Doenças por Armazenamento dos Lisossomos/patologia
Alvo Mecanístico do Complexo 1 de Rapamicina
Camundongos
Camundongos Knockout
Complexos Multiproteicos/genética
Fosfatidilinositóis/genética
Fosfatidilinositóis/metabolismo
Fosforilação/genética
Fosforilação/efeitos da radiação
Serina-Treonina Quinases TOR/genética
Raios Ultravioleta
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Beclin-1); 0 (Becn1 protein, mouse); 0 (Multiprotein Complexes); 0 (Phosphatidylinositols); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171118
[Lr] Data última revisão:
171118
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170906
[St] Status:MEDLINE


  5 / 12711 MEDLINE  
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[PMID]:28851711
[Au] Autor:Gujas B; Cruz TMD; Kastanaki E; Vermeer JEM; Munnik T; Rodriguez-Villalon A
[Ad] Endereço:Department of Biology, Swiss Federal Institute of Technology (ETH) Zurich, CH-8092, Zurich, Switzerland.
[Ti] Título:Perturbing phosphoinositide homeostasis oppositely affects vascular differentiation in roots.
[So] Source:Development;144(19):3578-3589, 2017 10 01.
[Is] ISSN:1477-9129
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The plant vascular network consists of specialized phloem and xylem elements that undergo two distinct morphogenetic developmental programs to become transport-functional units. Whereas vacuolar rupture is a determinant step in protoxylem differentiation, protophloem elements never form a big central vacuole. Here, we show that a genetic disturbance of phosphatidylinositol 4,5-bis-phosphate [PtdIns(4,5)P ] homeostasis rewires cell trafficking towards the vacuole in roots. Consequently, an enhanced phosphoinositide-mediated vacuolar biogenesis correlates with premature programmed cell death (PCD) and secondary cell wall elaboration in xylem cells. By contrast, vacuolar fusion events in protophloem cells trigger the abnormal formation of big vacuoles, preventing cell clearance and tissue functionality. Removal of the inositol 5' phosphatase COTYLEDON VASCULAR PATTERN 2 from the plasma membrane (PM) by brefeldin A (BFA) treatment increases PtdIns(4,5)P content at the PM and disrupts protophloem continuity. Conversely, BFA application abolishes vacuolar fusion events in xylem tissue without preventing PCD, suggesting the existence of additional PtdIns(4,5)P -dependent cell death mechanisms. Overall, our data indicate that tight PM phosphoinositide homeostasis is required to modulate intracellular trafficking contributing to oppositely regulate vascular differentiation.
[Mh] Termos MeSH primário: Arabidopsis/citologia
Diferenciação Celular
Homeostase
Fosfatidilinositóis/metabolismo
Raízes de Plantas/citologia
Feixe Vascular de Plantas/citologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Arabidopsis/efeitos dos fármacos
Arabidopsis/metabolismo
Proteínas de Arabidopsis/metabolismo
Transporte Biológico/efeitos dos fármacos
Diferenciação Celular/efeitos dos fármacos
Membrana Celular/efeitos dos fármacos
Membrana Celular/metabolismo
Estradiol/farmacologia
Homeostase/efeitos dos fármacos
Espaço Intracelular/metabolismo
Floema/citologia
Floema/efeitos dos fármacos
Floema/metabolismo
Raízes de Plantas/efeitos dos fármacos
Raízes de Plantas/metabolismo
Feixe Vascular de Plantas/efeitos dos fármacos
Feixe Vascular de Plantas/metabolismo
Vacúolos/efeitos dos fármacos
Vacúolos/metabolismo
Xilema/citologia
Xilema/efeitos dos fármacos
Xilema/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Arabidopsis Proteins); 0 (Phosphatidylinositols); 4TI98Z838E (Estradiol)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171126
[Lr] Data última revisão:
171126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170831
[St] Status:MEDLINE
[do] DOI:10.1242/dev.155788


  6 / 12711 MEDLINE  
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Martínez, Denis
Texto completo
[PMID]:28760887
[Au] Autor:Martinez D; Langlois d'Estaintot B; Granier T; Tolchard J; Courrèges C; Prouzet-Mauléon V; Hugues M; Gallois B; Doignon F; Odaert B
[Ad] Endereço:Université de Bordeaux, Chimie et Biologie des Membranes et des Nano-objets, CNRS UMR 5248, Allée Geoffroy Saint Hilaire, 33600 Pessac Cedex, France.
[Ti] Título:Structural evidence of a phosphoinositide-binding site in the Rgd1-RhoGAP domain.
[So] Source:Biochem J;474(19):3307-3319, 2017 Sep 20.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Phosphoinositide lipids recruit proteins to the plasma membrane involved in the regulation of cytoskeleton organization and in signalling pathways that control cell polarity and growth. Among those, Rgd1p is a yeast GTPase-activating protein (GAP) specific for Rho3p and Rho4p GTPases, which control actin polymerization and stress signalling pathways. Phosphoinositides not only bind Rgd1p, but also stimulate its GAP activity on the membrane-anchored form of Rho4p. Both F-BAR (F-BAR FCH, and BAR) and RhoGAP domains of Rgd1p are involved in lipid interactions. In the Rgd1p-F-BAR domain, a phosphoinositide-binding site has been recently characterized. We report here the X-ray structure of the Rgd1p-RhoGAP domain, identify by NMR spectroscopy and confirm by docking simulations, a new but cryptic phosphoinositide-binding site, comprising contiguous A1, A1' and B helices. The addition of helix A1', unusual among RhoGAP domains, seems to be crucial for lipid interactions. Such a site was totally unexpected inside a RhoGAP domain, as it was not predicted from either the protein sequence or its three-dimensional structure. Phosphoinositide-binding sites in RhoGAP domains have been reported to correspond to polybasic regions, which are located at the unstructured flexible termini of proteins. Solid-state NMR spectroscopy experiments confirm the membrane interaction of the Rgd1p-RhoGAP domain upon the addition of PtdIns(4,5)P and indicate a slight membrane destabilization in the presence of the two partners.
[Mh] Termos MeSH primário: Proteínas Ativadoras de GTPase/química
Proteínas Ativadoras de GTPase/metabolismo
Fosfatidilinositóis/química
Fosfatidilinositóis/metabolismo
Proteínas de Saccharomyces cerevisiae/química
Proteínas de Saccharomyces cerevisiae/metabolismo
Saccharomyces cerevisiae/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Sítios de Ligação
Membrana Celular/metabolismo
Cristalografia por Raios X
Lipossomos/metabolismo
Espectroscopia de Ressonância Magnética
Modelos Biológicos
Simulação de Acoplamento Molecular
Domínios Proteicos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GTPase-Activating Proteins); 0 (Liposomes); 0 (Phosphatidylinositols); 0 (RGD1 protein, S cerevisiae); 0 (Saccharomyces cerevisiae Proteins); 0 (rho GTPase-activating protein)
[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:170802
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20170331


  7 / 12711 MEDLINE  
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[PMID]:28719181
[Au] Autor:Rynkiewicz MJ; Wu H; Cafarella TR; Nikolaidis NM; Head JF; Seaton BA; McCormack FX
[Ad] Endereço:Department of Physiology and Biophysics, Boston University School of Medicine , Boston, Massachusetts 02118, United States.
[Ti] Título:Differential Ligand Binding Specificities of the Pulmonary Collectins Are Determined by the Conformational Freedom of a Surface Loop.
[So] Source:Biochemistry;56(31):4095-4105, 2017 Aug 08.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lung surfactant proteins (SPs) play critical roles in surfactant function and innate immunity. SP-A and SP-D, members of the collectin family of C-type lectins, exhibit distinct ligand specificities, effects on surfactant structure, and host defense functions despite extensive structural homology. SP-A binds to dipalmitoylphosphatidylcholine (DPPC), the major surfactant lipid component, but not phosphatidylinositol (PI), whereas SP-D shows the opposite preference. Additionally, SP-A and SP-D recognize widely divergent pathogen-associated molecular patterns. Previous studies suggested that a ligand-induced surface loop conformational change unique to SP-A contributes to lipid binding affinity. To test this hypothesis and define the structural features of SP-A and SP-D that determine their ligand binding specificities, a structure-guided approach was used to introduce key features of SP-D into SP-A. A quadruple mutant (E171D/P175E/R197N/K203D) that introduced an SP-D-like loop-stabilizing calcium binding site into the carbohydrate recognition domain was found to interconvert SP-A ligand binding preferences to an SP-D phenotype, exchanging DPPC for PI specificity, and resulting in the loss of lipid A binding and the acquisition of more avid mannan binding properties. Mutants with constituent single or triple mutations showed alterations in their lipid and sugar binding properties that were intermediate between those of SP-A and SP-D. Structures of mutant complexes with inositol or methyl-mannose revealed an attenuation of the ligand-induced conformational change relative to wild-type SP-A. These studies suggest that flexibility in a key surface loop supports the distinctive lipid binding functions of SP-A, thus contributing to its multiple functions in surfactant structure and regulation, and host defense.
[Mh] Termos MeSH primário: Modelos Moleculares
Proteína A Associada a Surfactante Pulmonar/metabolismo
Proteína D Associada a Surfactante Pulmonar/metabolismo
[Mh] Termos MeSH secundário: 1,2-Dipalmitoilfosfatidilcolina/química
1,2-Dipalmitoilfosfatidilcolina/metabolismo
Substituição de Aminoácidos
Animais
Sítios de Ligação
Cristalografia por Raios X
Cinética
Lectinas Tipo C/química
Lectinas Tipo C/metabolismo
Ligantes
Lipídeo A/química
Lipídeo A/metabolismo
Lipossomos
Mutagênese Sítio-Dirigida
Mutação
Fosfatidilinositóis/química
Fosfatidilinositóis/metabolismo
Conformação Proteica
Domínios e Motivos de Interação entre Proteínas
Redobramento de Proteína
Estabilidade Proteica
Proteína A Associada a Surfactante Pulmonar/química
Proteína A Associada a Surfactante Pulmonar/genética
Proteína D Associada a Surfactante Pulmonar/química
Proteína D Associada a Surfactante Pulmonar/genética
Ratos
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lectins, C-Type); 0 (Ligands); 0 (Lipid A); 0 (Liposomes); 0 (Phosphatidylinositols); 0 (Pulmonary Surfactant-Associated Protein A); 0 (Pulmonary Surfactant-Associated Protein D); 0 (Recombinant Fusion Proteins); 2644-64-6 (1,2-Dipalmitoylphosphatidylcholine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170719
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.6b01313


  8 / 12711 MEDLINE  
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[PMID]:28718450
[Au] Autor:Grabon A; Orlowski A; Tripathi A; Vuorio J; Javanainen M; Róg T; Lönnfors M; McDermott MI; Siebert G; Somerharju P; Vattulainen I; Bankaitis VA
[Ad] Endereço:From the Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, Texas 77843.
[Ti] Título:Dynamics and energetics of the mammalian phosphatidylinositol transfer protein phospholipid exchange cycle.
[So] Source:J Biol Chem;292(35):14438-14455, 2017 Sep 01.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Phosphatidylinositol-transfer proteins (PITPs) regulate phosphoinositide signaling in eukaryotic cells. The defining feature of PITPs is their ability to exchange phosphatidylinositol (PtdIns) molecules between membranes, and this property is central to PITP-mediated regulation of lipid signaling. However, the details of the PITP-mediated lipid exchange cycle remain entirely obscure. Here, all-atom molecular dynamics simulations of the mammalian StART-like PtdIns/phosphatidylcholine (PtdCho) transfer protein PITPα, both on membrane bilayers and in solvated systems, informed downstream biochemical analyses that tested key aspects of the hypotheses generated by the molecular dynamics simulations. These studies provided five key insights into the PITPα lipid exchange cycle: (i) interaction of PITPα with the membrane is spontaneous and mediated by four specific protein substructures; (ii) the ability of PITPα to initiate closure around the PtdCho ligand is accompanied by loss of flexibility of two helix/loop regions, as well as of the C-terminal helix; (iii) the energy barrier of phospholipid extraction from the membrane is lowered by a network of hydrogen bonds between the lipid molecule and PITPα; (iv) the trajectory of PtdIns or PtdCho into and through the lipid-binding pocket is chaperoned by sets of PITPα residues conserved throughout the StART-like PITP family; and (v) conformational transitions in the C-terminal helix have specific functional involvements in PtdIns transfer activity. Taken together, these findings provide the first mechanistic description of key aspects of the PITPα PtdIns/PtdCho exchange cycle and offer a rationale for the high conservation of particular sets of residues across evolutionarily distant members of the metazoan StART-like PITP family.
[Mh] Termos MeSH primário: Bicamadas Lipídicas/metabolismo
Modelos Moleculares
Fosfatidilcolinas/metabolismo
Fosfatidilinositóis/metabolismo
Proteínas de Transferência de Fosfolipídeos/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Substituição de Aminoácidos
Animais
Apoproteínas/química
Apoproteínas/genética
Apoproteínas/metabolismo
Transporte Biológico
Biologia Computacional
Sequência Conservada
Transferência de Energia
Ligações de Hidrogênio
Ligantes
Bicamadas Lipídicas/química
Simulação de Dinâmica Molecular
Mutação de Sentido Incorreto
Fosfatidilcolinas/química
Fosfatidilinositóis/química
Proteínas de Transferência de Fosfolipídeos/química
Proteínas de Transferência de Fosfolipídeos/genética
Polimorfismo de Nucleotídeo Único
Conformação Proteica
Domínios e Motivos de Interação entre Proteínas
Ratos
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apoproteins); 0 (Ligands); 0 (Lipid Bilayers); 0 (Phosphatidylcholines); 0 (Phosphatidylinositols); 0 (Phospholipid Transfer Proteins); 0 (Pitpn protein, rat); 0 (Recombinant Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170719
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.791467


  9 / 12711 MEDLINE  
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[PMID]:28634262
[Au] Autor:Dickson EJ
[Ad] Endereço:Department of Physiology and Membrane Biology, School of Medicine, University of California Davis, Davis, CA ejdickson@ucdavis.edu.
[Ti] Título:RASSF4: Regulator of plasma membrane PI(4,5)P .
[So] Source:J Cell Biol;216(7):1879-1881, 2017 Jul 03.
[Is] ISSN:1540-8140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P ) is a negatively charged phospholipid that plays a major role in recruiting and regulating proteins at the plasma membrane-cytosol interface. In this issue, Chen et al. (2017. https://doi.org/10.1083/jcb.201606047) demonstrate that RAS association domain family 4 (RASSF4) positively influences PI(4,5)P synthesis through ARF6-dependent regulation of PIP5K.
[Mh] Termos MeSH primário: Membrana Celular
Fosfatidilinositol 4,5-Difosfato
[Mh] Termos MeSH secundário: Fosfatidilinositóis
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Phosphatidylinositol 4,5-Diphosphate); 0 (Phosphatidylinositols)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170622
[St] Status:MEDLINE
[do] DOI:10.1083/jcb.201706042


  10 / 12711 MEDLINE  
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[PMID]:28542875
[Au] Autor:Su K; Xu T; Yu Z; Zhu J; Zhang Y; Wu M; Xiong Y; Liu J; Xu J
[Ad] Endereço:School of Life Sciences, University of Science and Technology of China, Hefei, China.
[Ti] Título:Structure of the PX domain of SNX25 reveals a novel phospholipid recognition model by dimerization in the PX domain.
[So] Source:FEBS Lett;591(13):2011-2018, 2017 Jul.
[Is] ISSN:1873-3468
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:SNX25, a regulator of GPCR signaling-phox-homology (PX) domain containing sorting nexin (SNX) member, has been proposed to be involved in the lysosomal degradation of the transforming growth factor ß receptor and the development of temporal lobe epilepsy. Targeting to the endosomal membranes by the specific binding of phosphorylated phosphatidylinositols (PIPs) through the PX domain is critical for the function of SNXs. However, the mechanism for SNX25-PX targeting to the endosomes remains unclear. Here, we demonstrate that the PX domain of zebrafish SNX25 (zSNX25-PX) is capable of binding to PI3P only in its dimeric form. We also present the crystal structure of zSNX25-PX. Combined with biochemical experiments, we further identify a potential PI3P-binding region and propose a novel PI-binding model based on dimerization in the PX domain of SNXs.
[Mh] Termos MeSH primário: Fosfatidilinositóis/metabolismo
Multimerização Proteica
Nexinas de Classificação/genética
Nexinas de Classificação/metabolismo
Proteínas de Peixe-Zebra/química
Proteínas de Peixe-Zebra/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Simulação de Acoplamento Molecular
Ligação Proteica
Domínios Proteicos
Proteínas de Peixe-Zebra/genética
[Pt] Tipo de publicação:LETTER
[Nm] Nome de substância:
0 (Phosphatidylinositols); 0 (Snx25 protein, zebrafish); 0 (Sorting Nexins); 0 (Zebrafish Proteins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE
[do] DOI:10.1002/1873-3468.12688



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