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[PMID]:29323851
[Au] Autor:Borisevich SV; Marennikova SS; Stovba LF; Petrov AA; Krotvov VT; Makhlai AA
[Ti] Título:Buffalopox.
[So] Source:Vopr Virusol;61(5):200-4, 2016.
[Is] ISSN:0507-4088
[Cp] País de publicação:Russia (Federation)
[La] Idioma:eng
[Ab] Resumo:Buffalopox is a contagious viral disease affecting milch buffaloes (Bubalus Bubalis) and, rarely, cows. The disease has zoonotic implications, as outbreaks are frequently associated with human infections, particularly in the milkers. Buffalopox is associated with high morbidity (80%). The clinical symptoms of the disease are characterized by wartline lesions on the udder, teats, inguinal region, base of the ears, and over the parotid. In the severe form, generalized rash is observed. Although the disease does not lead to high mortality, it has an adverse effect on the productivity and working capacity of the animals resulting in large economic losses. The outbreaks of buffalopox occurred frequently in India, Pakistan, Bangladesh, Nepal, Iran, Egypt, and Indonesia, where buffaloes are reared as milch animals. The buffalopox is closely related with other Orthopoxviruses. In particular, it is close to the vaccinia virus. There is a view that the buffalopox virus might be derived from the vaccinia virus. It is possible that it became pathogenic to humans and animals through adaptive evolution of the genome by obtaining the virulence genes. PCR is performed for the C18L gene for the purpose of specific detection and differentiation of the buffalopox virus from other orthopoxviruses. The C18L gene encodes the ankyrin repeat protein, which determines the virus host range. The open reading frame of this gene is only 150-nucleotide long as against 453 nucleotide in the vaccinia virus, 756 - in the camelpox virus, and 759 - in the cowpox virus. It can be concluded that a systematic study based on the epidemiology of the virus, existence of reservoirs, biological transmission, and the molecular organization of the buffalopox virus from buffalo, cow, and humans may pave the way to a better understanding of the circulating virus and contribute to the control of the disease using the suitable diagnostic and prophylactic measures.
[Mh] Termos MeSH primário: Vírus da Varíola Bovina/genética
Varíola Bovina/epidemiologia
Surtos de Doenças
Vírus Vaccinia/genética
Vaccinia/veterinária
Zoonoses/epidemiologia
[Mh] Termos MeSH secundário: Animais
Repetição de Anquirina
Ásia Ocidental/epidemiologia
Búfalos/virologia
Bovinos
Varíola Bovina/transmissão
Varíola Bovina/virologia
Vírus da Varíola Bovina/classificação
Vírus da Varíola Bovina/isolamento & purificação
DNA Viral/genética
Oriente Médio/epidemiologia
Filogenia
Vaccinia/epidemiologia
Vaccinia/transmissão
Vaccinia/virologia
Vírus Vaccinia/classificação
Vírus Vaccinia/isolamento & purificação
Proteínas Virais/genética
Zoonoses/transmissão
Zoonoses/virologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (DNA, Viral); 0 (Viral Proteins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180112
[St] Status:MEDLINE


  2 / 620 MEDLINE  
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[PMID]:29175332
[Au] Autor:Kozlov G; Wong K; Wang W; Skubák P; Muñoz-Escobar J; Liu Y; Siddiqui N; Pannu NS; Gehring K
[Ad] Endereço:Department of Biochemistry, Groupe de recherche axé sur la structure des protéines, McGill University, Montreal, QC H3G 0B1, Canada.
[Ti] Título:Ankyrin repeats as a dimerization module.
[So] Source:Biochem Biophys Res Commun;495(1):1002-1007, 2018 01 01.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Legionella pneumophila is a pathogen, causing severe pneumonia in humans called Legionnaires' disease. AnkC (LegA12) is a poorly characterized 495-residue effector protein conserved in multiple Legionella species. Here, we report the crystal structure of a C-terminally truncated AnkC (2-384) at 3.2 Å resolution. The structure shows seven ankyrin repeats (ARs) with unique structural features. AnkC forms a dimer along the outer surface of loops between ARs. The dimer exists both in the crystal form and in solution, as shown by analytical ultracentrifugation. This is the first example of ARs as a dimerization module as opposed to solely a protein interaction domain. In addition, a novel α-helix insert between AR3-AR4 is positioned across the surface opposite the ankyrin groove. Sequence conservation suggests that the ankyrin groove of AnkC is a functional site that interacts with binding targets. This ankyrin domain structure is an important step towards a functional characterization of AnkC.
[Mh] Termos MeSH primário: Repetição de Anquirina
Anquirinas/química
Anquirinas/ultraestrutura
Modelos Químicos
Modelos Moleculares
Multimerização Proteica
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Sítios de Ligação
Simulação por Computador
Sequência Conservada
Legionella pneumophila/metabolismo
Dados de Sequência Molecular
Ligação Proteica
Conformação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Ankyrins)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180105
[Lr] Data última revisão:
180105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE


  3 / 620 MEDLINE  
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[PMID]:29033321
[Au] Autor:Wojtas MN; Pandey RR; Mendel M; Homolka D; Sachidanandam R; Pillai RS
[Ad] Endereço:Department of Molecular Biology, University of Geneva, 30 Quai Ernest-Ansermet, CH-1211 Geneva 4, Switzerland; European Molecular Biology Laboratory, Grenoble Outstation, 71 Avenue des Martyrs, 38042 Grenoble, France.
[Ti] Título:Regulation of m A Transcripts by the 3'→5' RNA Helicase YTHDC2 Is Essential for a Successful Meiotic Program in the Mammalian Germline.
[So] Source:Mol Cell;68(2):374-387.e12, 2017 Oct 19.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:N -methyladenosine (m A) is an essential internal RNA modification that is critical for gene expression control in most organisms. Proteins with a YTH domain recognize m A marks and are mediators of molecular functions like RNA splicing, mRNA decay, and translation control. Here we demonstrate that YTH domain-containing 2 (YTHDC2) is an m A reader that is essential for male and female fertility in mice. High-throughput mapping of the m A transcriptome and expression analysis in the Yhtdc2 mutant testes reveal an upregulation of m A-enriched transcripts. Our biochemical studies indicate that YTHDC2 is an RNA-induced ATPase with a 3'→5' RNA helicase activity. Furthermore, YTHDC2 recruits the 5'→3' exoribonuclease XRN1 via Ankyrin repeats that are inserted in between the RecA modules of the RNA helicase domain. Our studies reveal a role for YTHDC2 in modulating the levels of m A-modified germline transcripts to maintain a gene expression program that is conducive for progression through meiosis.
[Mh] Termos MeSH primário: Adenosina/análogos & derivados
Regulação da Expressão Gênica/fisiologia
Meiose/fisiologia
RNA Helicases/metabolismo
RNA Mensageiro/metabolismo
[Mh] Termos MeSH secundário: Adenosina/genética
Adenosina/metabolismo
Animais
Repetição de Anquirina
Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Exorribonucleases/genética
Exorribonucleases/metabolismo
Masculino
Camundongos
Camundongos Mutantes
Domínios Proteicos
RNA Helicases/genética
RNA Mensageiro/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (RNA, Messenger); 1867-73-8 (N(6)-methyladenosine); EC 3.1.- (Exoribonucleases); EC 3.1.- (Xrn1 protein, mouse); EC 3.6.4.13 (RNA Helicases); K72T3FS567 (Adenosine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171017
[St] Status:MEDLINE


  4 / 620 MEDLINE  
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[PMID]:28882895
[Au] Autor:Lemonidis K; MacLeod R; Baillie GS; Chamberlain LH
[Ad] Endereço:From The Strathclyde Institute of Pharmacy and Biomedical Sciences, 161 Cathedral Street, University of Strathclyde, Glasgow G4 0RE and kimon.lemonidis@strath.ac.uk.
[Ti] Título:Peptide array-based screening reveals a large number of proteins interacting with the ankyrin-repeat domain of the zDHHC17 -acyltransferase.
[So] Source:J Biol Chem;292(42):17190-17202, 2017 Oct 20.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:zDHHC -acyltransferases are enzymes catalyzing protein -acylation, a common post-translational modification on proteins frequently affecting their membrane targeting and trafficking. The ankyrin repeat (AR) domain of zDHHC17 (HIP14) and zDHHC13 (HIP14L) -acyltransferases, which is involved in both substrate recruitment and -acylation-independent functions, was recently shown to bind at least six proteins, by specific recognition of a consensus sequence in them. To further refine the rules governing binding to the AR of zDHHC17, we employed peptide arrays based on zDHHC AR-binding motif (zDABM) sequences of synaptosomal-associated protein 25 (SNAP25) and cysteine string protein α (CSPα). Quantitative comparisons of the binding preferences of 400 peptides allowed us to construct a position-specific scoring matrix (PSSM) for zDHHC17 AR binding, with which we predicted and subsequently validated many putative zDHHC17 interactors. We identified 95 human zDABM sequences with unexpected versatility in amino acid usage; these sequences were distributed among 90 proteins, of which 62 have not been previously implicated in zDHHC17/13 binding. These zDABM-containing proteins included all family members of the SNAP25, sprouty, cornifelin, ankyrin, and SLAIN-motif containing families; seven endogenous Gag polyproteins sharing the same binding sequence; and several proteins involved in cytoskeletal organization, cell communication, and regulation of signaling. A dozen of the zDABM-containing proteins had more than one zDABM sequence, whereas isoform-specific binding to the AR of zDHHC17 was identified for the Ena/VASP-like protein. The large number of zDABM sequences within the human proteome suggests that zDHHC17 may be an interaction hub regulating many cellular processes.
[Mh] Termos MeSH primário: Aciltransferases/metabolismo
Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Proteínas do Tecido Nervoso/metabolismo
Proteoma/metabolismo
[Mh] Termos MeSH secundário: Aciltransferases/química
Proteínas Adaptadoras de Transdução de Sinal/química
Repetição de Anquirina
Linhagem Celular
Proteínas de Choque Térmico HSP40/química
Proteínas de Choque Térmico HSP40/metabolismo
Seres Humanos
Proteínas de Membrana/química
Proteínas de Membrana/metabolismo
Proteínas do Tecido Nervoso/química
Peptídeos/química
Peptídeos/metabolismo
Análise Serial de Proteínas/métodos
Ligação Proteica
Proteoma/química
Proteína 25 Associada a Sinaptossoma/química
Proteína 25 Associada a Sinaptossoma/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (HSP40 Heat-Shock Proteins); 0 (Membrane Proteins); 0 (Nerve Tissue Proteins); 0 (Peptides); 0 (Proteome); 0 (SNAP25 protein, human); 0 (Synaptosomal-Associated Protein 25); 0 (cysteine string protein); EC 2.3.- (Acyltransferases); EC 2.3.1.- (ZDHHC17 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170909
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.799650


  5 / 620 MEDLINE  
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[PMID]:28806065
[Au] Autor:Deyev S; Proshkina G; Ryabova A; Tavanti F; Menziani MC; Eidelshtein G; Avishai G; Kotlyar A
[Ad] Endereço:Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences , Miklukho-Maklaya St, 16/10, Moscow 117997, Russia.
[Ti] Título:Synthesis, Characterization, and Selective Delivery of DARPin-Gold Nanoparticle Conjugates to Cancer Cells.
[So] Source:Bioconjug Chem;28(10):2569-2574, 2017 Oct 18.
[Is] ISSN:1520-4812
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We demonstrate that the designed ankyrin repeat protein (DARPin)_9-29, which specifically targets human epidermal growth factor receptor 2 (HER 2), binds tightly to gold nanoparticles (GNPs). Binding of the protein strongly increases the colloidal stability of the particles. The results of experimental analysis and molecular dynamics simulations show that approximately 35 DARPin_9-29 molecules are bound to the surface of a 5 nm GNP and that the binding does not involve the receptor-binding domain of the protein. The confocal fluorescent microscopy studies show that the DARPin-coated GNP conjugate specifically interacts with the surface of human cancer cells overexpressing epidermal growth factor receptor 2 (HER2) and enters the cells by endocytosis. The high stability under physiological conditions and high affinity to the receptors overexpressed by cancer cells make conjugates of plasmonic gold nanostructures with DARPin molecules promising candidates for cancer therapy.
[Mh] Termos MeSH primário: Repetição de Anquirina
Imunoconjugados/química
Imunoconjugados/metabolismo
Nanopartículas Metálicas/química
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Técnicas de Química Sintética
Seres Humanos
Imunoconjugados/imunologia
Modelos Moleculares
Receptor ErbB-2/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Immunoconjugates); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (Receptor, ErbB-2)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170815
[St] Status:MEDLINE
[do] DOI:10.1021/acs.bioconjchem.7b00410


  6 / 620 MEDLINE  
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[PMID]:28639341
[Au] Autor:Jost C; Stüber JC; Honegger A; Wu Y; Batyuk A; Plückthun A
[Ad] Endereço:Department of Biochemistry, University of Zurich, 8057, Zurich, Switzerland.
[Ti] Título:Rigidity of the extracellular part of HER2: Evidence from engineering subdomain interfaces and shared-helix DARPin-DARPin fusions.
[So] Source:Protein Sci;26(9):1796-1806, 2017 Sep.
[Is] ISSN:1469-896X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The second member of the human ErbB family of receptor tyrosine kinases, HER2/hErbB2, is regarded as an exceptional case: The four extracellular subdomains could so far only be found in one fixed overall conformation, designated "open" and resembling the ligand-bound form of the other ErbB receptors. It thus appears to be different from the extracellular domains of the other family members that show inter-subdomain flexibility and exist in a "tethered" form in the absence of ligand. For HER2, there was so far no direct evidence for such a tethered conformation on the cell surface. Nonetheless, alternative conformations of HER2 in vivo could so far not be excluded. We now demonstrate the rigidity of HER2 on the surface of tumor cells by employing two orthogonal approaches of protein engineering: To directly test the potential of the extracellular domain of HER2 to adopt a pseudo-tethered conformation on the cell surface, we first designed HER2 variants with a destabilized interface between extracellular subdomains I and III that would favor deviation from the "open" conformation. Secondly, we used differently shaped versions of a Designed Ankyrin Repeat Protein (DARPin) fusion, recognizing subdomain I of HER2, devised to work as probes for a putative pseudo-tethered extracellular domain of HER2. Combining our approaches, we exclude, on live cells and in vitro, that significant proportions of HER2 deviate from the "open" conformation.
[Mh] Termos MeSH primário: Repetição de Anquirina/genética
Engenharia de Proteínas/métodos
Receptor ErbB-2/química
Receptor ErbB-2/metabolismo
Proteínas Recombinantes de Fusão/química
[Mh] Termos MeSH secundário: Linhagem Celular
Espaço Extracelular/química
Seres Humanos
Modelos Moleculares
Mutação
Ligação Proteica
Domínios Proteicos
Receptor ErbB-2/genética
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Recombinant Fusion Proteins); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (Receptor, ErbB-2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170623
[St] Status:MEDLINE
[do] DOI:10.1002/pro.3216


  7 / 620 MEDLINE  
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[PMID]:28619731
[Au] Autor:Xu D; Liu J; Fu T; Shan B; Qian L; Pan L; Yuan J
[Ad] Endereço:Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Pudong, Shanghai 201210, China.
[Ti] Título:USP25 regulates Wnt signaling by controlling the stability of tankyrases.
[So] Source:Genes Dev;31(10):1024-1035, 2017 May 15.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aberrant activation of the Wnt signaling pathway plays an important role in human cancer development. Wnt signaling is negatively regulated by Axin, a scaffolding protein that controls a rate-limiting step in the destruction of ß-catenin, the central activator of the Wnt pathway. In Wnt-stimulated cells, Axin is rapidly modified by tankyrase-mediated poly(ADP-ribosyl)ation, which promotes the proteolysis of Axin and consequent stabilization of ß-catenin. Thus, regulation of the levels and activity of tankyrases is mechanistically important in controlling Wnt signaling. Here, we identify ubiquitin-specific protease 25 (USP25) as a positive regulator of Wnt/ß-catenin signaling. We found that USP25 directly interacted with tankyrases to promote their deubiquitination and stabilization. We demonstrated that USP25 deficiency could promote the degradation of tankyrases and consequent stabilization of Axin to antagonize Wnt signaling. We further characterized the interaction between TNKS1 and USP25 by X-ray crystal structure determination. Our results provide important new insights into the molecular mechanism that regulates the turnover of tankyrases and the possibility of targeting the stability of tankyrases by antagonizing their interaction with USP25 to modulate the Wnt/ß-catenin pathway.
[Mh] Termos MeSH primário: Estabilidade Enzimática/genética
Tanquirases/metabolismo
Ubiquitina Tiolesterase/metabolismo
Via de Sinalização Wnt/fisiologia
[Mh] Termos MeSH secundário: Repetição de Anquirina
Proteína Axina/metabolismo
Linhagem Celular
Cristalografia por Raios X
Células HCT116
Células HEK293
Seres Humanos
Mutação
Ligação Proteica
Tanquirases/química
Ubiquitina Tiolesterase/química
Ubiquitina Tiolesterase/genética
Via de Sinalização Wnt/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Axin Protein); EC 2.4.2.30 (Tankyrases); EC 2.4.4.30 (TNKS protein, human); EC 3.1.2.15 (USP25 protein, human); EC 3.4.19.12 (Ubiquitin Thiolesterase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170617
[St] Status:MEDLINE
[do] DOI:10.1101/gad.300889.117


  8 / 620 MEDLINE  
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[PMID]:28615162
[Au] Autor:Wette SG; Smith HK; Lamb GD; Murphy RM
[Ad] Endereço:Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia.
[Ti] Título:Characterization of muscle ankyrin repeat proteins in human skeletal muscle.
[So] Source:Am J Physiol Cell Physiol;313(3):C327-C339, 2017 Sep 01.
[Is] ISSN:1522-1563
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Muscle ankyrin repeat proteins (MARPs) are a family of titin-associated, stress-response molecules and putative transducers of stretch-induced signaling in skeletal muscle. In cardiac muscle, cardiac ankyrin repeat protein (CARP) and diabetes-related ankyrin repeat protein (DARP) reportedly redistribute from binding sites on titin to the nucleus following a prolonged stretch. However, it is unclear whether ankyrin repeat domain protein 2 (Ankrd 2) shows comparable stretch-induced redistribution to the nucleus. We measured the following in rested human skeletal muscle: ) the absolute amount of MARPs and ) the distribution of Ankrd 2 and DARP in both single fibers and whole muscle preparations. In absolute amounts, Ankrd 2 is the most abundant MARP in human skeletal muscle, there being ~3.1 µmol/kg, much greater than DARP and CARP (~0.11 and ~0.02 µmol/kg, respectively). All DARP was found to be tightly bound at cytoskeletal (or possibly nuclear) sites. In contrast, ~70% of the total Ankrd 2 is freely diffusible in the cytosol [including virtually all of the phosphorylated (p)Ankrd 2-Ser99 form], ~15% is bound to non-nuclear membranes, and ~15% is bound at cytoskeletal sites, likely at the N2A region of titin. These data are not consistent with the proposal that Ankrd 2, per se, or pAnkrd 2-Ser99 mediates stretch-induced signaling in skeletal muscle, dissociating from titin and translocating to the nucleus, because the majority of these forms of Ankrd 2 are already free in the cytosol. It will be necessary to show that the titin-associated Ankrd 2 is modified by stretch in some as-yet-unidentified way, distinct from the diffusible pool, if it is to act as a stretch-sensitive signaling molecule.
[Mh] Termos MeSH primário: Repetição de Anquirina/fisiologia
Proteínas Musculares/metabolismo
Músculo Esquelético/metabolismo
Proteínas Nucleares/metabolismo
Proteínas Repressoras/metabolismo
[Mh] Termos MeSH secundário: Adulto
Animais
Feminino
Seres Humanos
Ratos
Ratos Sprague-Dawley
Distribuição Tecidual
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ANKRD23 protein, human); 0 (Ankrd1 protein, rat); 0 (Ankrd2 protein, rat); 0 (Muscle Proteins); 0 (Nuclear Proteins); 0 (Repressor Proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171005
[Lr] Data última revisão:
171005
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170616
[St] Status:MEDLINE
[do] DOI:10.1152/ajpcell.00077.2017


  9 / 620 MEDLINE  
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[PMID]:28526749
[Au] Autor:Pasquali CC; Islam Z; Adamoski D; Ferreira IM; Righeto RD; Bettini J; Portugal RV; Yue WW; Gonzalez A; Dias SMG; Ambrosio ALB
[Ad] Endereço:From the Laboratório Nacional de Biociências, Centro Nacional de Pesquisa em Energia e Materiais, Campinas, São Paulo 13083-970, Brazil.
[Ti] Título:The origin and evolution of human glutaminases and their atypical C-terminal ankyrin repeats.
[So] Source:J Biol Chem;292(27):11572-11585, 2017 Jul 07.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:On the basis of tissue-specific enzyme activity and inhibition by catalytic products, Hans Krebs first demonstrated the existence of multiple glutaminases in mammals. Currently, two human genes are known to encode at least four glutaminase isoforms. However, the phylogeny of these medically relevant enzymes remains unclear, prompting us to investigate their origin and evolution. Using prokaryotic and eukaryotic glutaminase sequences, we built a phylogenetic tree whose topology suggested that the multidomain architecture was inherited from bacterial ancestors, probably simultaneously with the hosting of the proto-mitochondrion endosymbiont. We propose an evolutionary model wherein the appearance of the most active enzyme isoform, glutaminase C (GAC), which is expressed in many cancers, was a late retrotransposition event that occurred in fishes from the Chondrichthyes class. The ankyrin (ANK) repeats in the glutaminases were acquired early in their evolution. To obtain information on ANK folding, we solved two high-resolution structures of the ANK repeat-containing C termini of both kidney-type glutaminase (KGA) and GLS2 isoforms (glutaminase B and liver-type glutaminase). We found that the glutaminase ANK repeats form unique intramolecular contacts through two highly conserved motifs; curiously, this arrangement occludes a region usually involved in ANK-mediated protein-protein interactions. We also solved the crystal structure of full-length KGA and present a small-angle X-ray scattering model for full-length GLS2. These structures explain these proteins' compromised ability to assemble into catalytically active supra-tetrameric filaments, as previously shown for GAC. Collectively, these results provide information about glutaminases that may aid in the design of isoform-specific glutaminase inhibitors.
[Mh] Termos MeSH primário: Evolução Molecular
Glutaminase
Modelos Genéticos
Modelos Moleculares
[Mh] Termos MeSH secundário: Repetição de Anquirina
Cristalografia por Raios X
Glutaminase/química
Glutaminase/genética
Seres Humanos
Isoenzimas/química
Isoenzimas/genética
Domínios Proteicos
Estrutura Quaternária de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Isoenzymes); EC 3.5.1.2 (GLS2 protein, human); EC 3.5.1.2 (Glutaminase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170714
[Lr] Data última revisão:
170714
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170521
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.787291


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[PMID]:28302725
[Au] Autor:van Haaften-Visser DY; Harakalova M; Mocholi E; van Montfrans JM; Elkadri A; Rieter E; Fiedler K; van Hasselt PM; Triffaux EMM; van Haelst MM; Nijman IJ; Kloosterman WP; Nieuwenhuis EES; Muise AM; Cuppen E; Houwen RHJ; Coffer PJ
[Ad] Endereço:From the Division of Pediatrics, Wilhelmina Children's Hospital.
[Ti] Título:Ankyrin repeat and zinc-finger domain-containing 1 mutations are associated with infantile-onset inflammatory bowel disease.
[So] Source:J Biol Chem;292(19):7904-7920, 2017 May 12.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Infantile-onset inflammatory bowel disease (IO IBD) is an invalidating illness with an onset before 2 years of age and has a complex pathophysiology in which genetic factors are important. Homozygosity mapping and whole-exome sequencing in an IO IBD patient and subsequent sequencing of the candidate gene in 12 additional IO IBD patients revealed two patients with two mutated ankyrin repeat and zinc-finger domain-containing 1 ( ) alleles (homozygous R585Q mutation and compound heterozygous E152K and V32_Q87del mutations, respectively) and two patients with one mutated allele. Although the function of ANKZF1 in mammals had not been previously evaluated, we show that ANKZF1 has an indispensable role in the mitochondrial response to cellular stress. ANKZF1 is located diffusely in the cytoplasm and translocates to the mitochondria upon cellular stress. ANKZF1 depletion reduces mitochondrial integrity and mitochondrial respiration under conditions of cellular stress. The mutations identified in IO IBD patients with two mutated alleles result in dysfunctional ANKZF1, as shown by an increased level of apoptosis in patients' lymphocytes, a decrease in mitochondrial respiration in patient fibroblasts with a homozygous R585Q mutation, and an inability of ANKZF1 R585Q and E152K to rescue the phenotype of yeast deficient in Vms1, the yeast homologue of ANKZF1. These data indicate that loss-of-function mutations in result in deregulation of mitochondrial integrity, and this may play a pathogenic role in the development of IO IBD.
[Mh] Termos MeSH primário: Repetição de Anquirina/genética
Proteínas de Transporte/genética
Doenças Inflamatórias Intestinais/genética
Dedos de Zinco
[Mh] Termos MeSH secundário: Idade de Início
Alelos
Apoptose
Proteínas de Transporte/metabolismo
Linhagem Celular Tumoral
Pré-Escolar
Exoma
Feminino
Fibroblastos/metabolismo
Genoma Humano
Células HEK293
Homozigoto
Seres Humanos
Lactente
Inflamação
Doenças Inflamatórias Intestinais/metabolismo
Linfócitos/citologia
Masculino
Mitocôndrias/metabolismo
Mutação
Fenótipo
RNA Interferente Pequeno/metabolismo
Análise de Sequência de DNA
Zinco/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ANKZF1 protein, human); 0 (Carrier Proteins); 0 (RNA, Small Interfering); J41CSQ7QDS (Zinc)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170318
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.772038



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