Base de dados : MEDLINE
Pesquisa : G02.111.570.820.709.275.500.869.500 [Categoria DeCS]
Referências encontradas : 17 [refinar]
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  1 / 17 MEDLINE  
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[PMID]:28460014
[Au] Autor:Wu X; Wang SH; Sun J; Krainer AR; Hua Y; Prior TW
[Ad] Endereço:Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China.
[Ti] Título:A-44G transition in SMN2 intron 6 protects patients with spinal muscular atrophy.
[So] Source:Hum Mol Genet;26(14):2768-2780, 2017 07 15.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Spinal muscular atrophy (SMA) is a neuromuscular disease caused by reduced expression of survival of motor neuron (SMN), a protein expressed in humans by two paralogous genes, SMN1 and SMN2. These genes are nearly identical, except for 10 single-nucleotide differences and a 5-nucleotide insertion in SMN2. SMA is subdivided into four main types, with type I being the most severe. SMN2 copy number is a key positive modifier of the disease, but it is not always inversely correlated with clinical severity. We previously reported the c.859G > C variant in SMN2 exon 7 as a positive modifier in several patients. We have now identified A-44G as an additional positive disease modifier, present in a group of patients carrying 3 SMN2 copies but displaying milder clinical phenotypes than other patients with the same SMN2 copy number. One of the three SMN2 copies appears to have been converted from SMN1, but except for the C6T transition, no other changes were detected. Analyzed with minigenes, SMN1C6T displayed a ∼20% increase in exon 7 inclusion, compared to SMN2. Through systematic mutagenesis, we found that the improvement in exon 7 splicing is mainly attributable to the A-44G transition in intron 6. Using RNA-affinity chromatography and mass spectrometry, we further uncovered binding of the RNA-binding protein HuR to the -44 region, where it acts as a splicing repressor. The A-44G change markedly decreases the binding affinity of HuR, resulting in a moderate increase in exon 7 inclusion.
[Mh] Termos MeSH primário: Atrofia Muscular Espinal/genética
[Mh] Termos MeSH secundário: Animais
Células COS
Cercopithecus aethiops
Proteína Semelhante a ELAV 1/metabolismo
Éxons
Células HEK293
Células HeLa
Seres Humanos
Íntrons
Atrofia Muscular Espinal/metabolismo
Ligação Proteica
RNA/genética
Motivo de Reconhecimento de RNA
Processamento de RNA
Proteína 1 de Sobrevivência do Neurônio Motor/genética
Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo
Proteína 2 de Sobrevivência do Neurônio Motor/genética
Proteína 2 de Sobrevivência do Neurônio Motor/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (ELAV-Like Protein 1); 0 (ELAVL1 protein, human); 0 (SMN1 protein, human); 0 (SMN2 protein, human); 0 (Survival of Motor Neuron 1 Protein); 0 (Survival of Motor Neuron 2 Protein); 63231-63-0 (RNA)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180225
[Lr] Data última revisão:
180225
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170502
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddx166


  2 / 17 MEDLINE  
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[PMID]:29050934
[Au] Autor:Wang L; Yan F
[Ad] Endereço:Division of Nephrology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, United States.
[Ti] Título:Molecular insights into the specific recognition between the RNA binding domain qRRM2 of hnRNP F and G-tract RNA: A molecular dynamics study.
[So] Source:Biochem Biophys Res Commun;494(1-2):95-100, 2017 Dec 09.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Heterogeneous nuclear ribonucleoprotein F (hnRNP F) controls the expression of various genes through regulating the alternative splicing of pre-mRNAs in the nucleus. It uses three quasi-RNA recognition motifs (qRRMs) to recognize G-tract RNA which contains at least three consecutive guanines. The structures containing qRRMs of hnRNP F in complex with G-tract RNA have been determined by nuclear magnetic resonance (NMR) spectroscopy, shedding light on the recognition mechanism of qRRMs with G-tract RNA. However, knowledge of the recognition details is still lacking. To investigate how qRRMs specifically bind with G-tract RNA and how the mutations of any guanine to an adenine in the G-tract affect the binding, molecular dynamics simulations with binding free energy analysis were performed based on the NMR structure of qRRM2 in complex with G-tract RNA. Simulation results demonstrate that qRRM2 binds strongly with G-tract RNA, but any mutation of the G-tract leads to a drastic reduction of the binding free energy. Further comparisons of the energetic components reveal that van der Waals and non-polar interactions play essential roles in the binding between qRRM2 and G-tract RNA, but the interactions are weakened by the effect of RNA mutations. Structural and dynamical analyses indicate that when qRRM2 binds with G-tract RNA, both qRRM2 and G-tract maintain stabilized structures and dynamics; however, the stability is disrupted by the mutations of the G-tract. These results provide novel insights into the recognition mechanism of qRRM2 with G-tract RNA that are not elucidated by the NMR technique.
[Mh] Termos MeSH primário: Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/química
Ribonucleoproteínas Nucleares Heterogêneas Grupo F-H/metabolismo
RNA/química
RNA/metabolismo
[Mh] Termos MeSH secundário: Sequência de Bases
Sítios de Ligação
Seres Humanos
Simulação de Dinâmica Molecular
Mutação
Ressonância Magnética Nuclear Biomolecular
Conformação de Ácido Nucleico
Ligação Proteica
Conformação Proteica
Estabilidade Proteica
RNA/genética
Motivo de Reconhecimento de RNA
Motivos de Ligação ao RNA
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Heterogeneous-Nuclear Ribonucleoprotein Group F-H); 63231-63-0 (RNA)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171021
[St] Status:MEDLINE


  3 / 17 MEDLINE  
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[PMID]:28542332
[Au] Autor:Kamina AD; Williams N
[Ad] Endereço:Department of Microbiology and Immunology and Witebsky Center for Microbial Pathogenesis and Immunology, University at Buffalo, Buffalo, New York, United States of America.
[Ti] Título:Non-canonical binding interactions of the RNA recognition motif (RRM) domains of P34 protein modulate binding within the 5S ribonucleoprotein particle (5S RNP).
[So] Source:PLoS One;12(5):e0177890, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RNA binding proteins are involved in many aspects of RNA metabolism. In Trypanosoma brucei, our laboratory has identified two trypanosome-specific RNA binding proteins P34 and P37 that are involved in the maturation of the 60S subunit during ribosome biogenesis. These proteins are part of the T. brucei 5S ribonucleoprotein particle (5S RNP) and P34 binds to 5S ribosomal RNA (rRNA) and ribosomal protein L5 through its N-terminus and its RNA recognition motif (RRM) domains. We generated truncated P34 proteins to determine these domains' interactions with 5S rRNA and L5. Our analyses demonstrate that RRM1 of P34 mediates the majority of binding with 5S rRNA and the N-terminus together with RRM1 contribute the most to binding with L5. We determined that the consensus ribonucleoprotein (RNP) 1 and 2 sequences, characteristic of canonical RRM domains, are not fully conserved in the RRM domains of P34. However, the aromatic amino acids previously described to mediate base stacking interactions with their RNA target are conserved in both of the RRM domains of P34. Surprisingly, mutation of these aromatic residues did not disrupt but instead enhanced 5S rRNA binding. However, we identified four arginine residues located in RRM1 of P34 that strongly impact L5 binding. These mutational analyses of P34 suggest that the binding site for 5S rRNA and L5 are near each other and specific residues within P34 regulate the formation of the 5S RNP. These studies show the unique way that the domains of P34 mediate binding with the T. brucei 5S RNP.
[Mh] Termos MeSH primário: Motivo de Reconhecimento de RNA
Proteínas de Ligação a RNA/química
Proteínas de Ligação a RNA/metabolismo
Ribonucleoproteínas/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Sequência Consenso
Modelos Moleculares
Mutação
Ligação Proteica
Domínios Proteicos
RNA Ribossômico 5S/metabolismo
Ribonucleoproteínas/química
Ribonucleoproteínas/genética
Proteínas Ribossômicas/química
Proteínas Ribossômicas/metabolismo
Trypanosoma brucei brucei/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Ribosomal, 5S); 0 (RNA-Binding Proteins); 0 (Ribonucleoproteins); 0 (Ribosomal Proteins); 0 (p34 protein, Trypanosoma brucei); 0 (ribosomal protein L5)
[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:170526
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0177890


  4 / 17 MEDLINE  
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[PMID]:28505313
[Au] Autor:Krepl M; Blatter M; Cléry A; Damberger FF; Allain FHT; Sponer J
[Ad] Endereço:Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, 612 65 Brno, Czech Republic.
[Ti] Título:Structural study of the Fox-1 RRM protein hydration reveals a role for key water molecules in RRM-RNA recognition.
[So] Source:Nucleic Acids Res;45(13):8046-8063, 2017 Jul 27.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The Fox-1 RNA recognition motif (RRM) domain is an important member of the RRM protein family. We report a 1.8 Å X-ray structure of the free Fox-1 containing six distinct monomers. We use this and the nuclear magnetic resonance (NMR) structure of the Fox-1 protein/RNA complex for molecular dynamics (MD) analyses of the structured hydration. The individual monomers of the X-ray structure show diverse hydration patterns, however, MD excellently reproduces the most occupied hydration sites. Simulations of the protein/RNA complex show hydration consistent with the isolated protein complemented by hydration sites specific to the protein/RNA interface. MD predicts intricate hydration sites with water-binding times extending up to hundreds of nanoseconds. We characterize two of them using NMR spectroscopy, RNA binding with switchSENSE and free-energy calculations of mutant proteins. Both hydration sites are experimentally confirmed and their abolishment reduces the binding free-energy. A quantitative agreement between theory and experiment is achieved for the S155A substitution but not for the S122A mutant. The S155 hydration site is evolutionarily conserved within the RRM domains. In conclusion, MD is an effective tool for predicting and interpreting the hydration patterns of protein/RNA complexes. Hydration is not easily detectable in NMR experiments but can affect stability of protein/RNA complexes.
[Mh] Termos MeSH primário: Fatores de Processamento de RNA/química
Fatores de Processamento de RNA/metabolismo
RNA/metabolismo
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Sítios de Ligação
Cristalografia por Raios X
Seres Humanos
Simulação de Dinâmica Molecular
Mutagênese Sítio-Dirigida
Ressonância Magnética Nuclear Biomolecular
Motivo de Reconhecimento de RNA/genética
Fatores de Processamento de RNA/genética
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Água/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RBFOX1 protein, human); 0 (RNA Splicing Factors); 0 (Recombinant Proteins); 059QF0KO0R (Water); 63231-63-0 (RNA)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170516
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx418


  5 / 17 MEDLINE  
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[PMID]:28184449
[Au] Autor:Waris S; García-Mauriño SM; Sivakumaran A; Beckham SA; Loughlin FE; Gorospe M; Díaz-Moreno I; Wilce MCJ; Wilce JA
[Ad] Endereço:Monash Biomedicine Discovery Institute, Department of Biochemistry & Molecular Biology, Monash University, Victoria 3800, Australia.
[Ti] Título:TIA-1 RRM23 binding and recognition of target oligonucleotides.
[So] Source:Nucleic Acids Res;45(8):4944-4957, 2017 May 05.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:TIA-1 (T-cell restricted intracellular antigen-1) is an RNA-binding protein involved in splicing and translational repression. It mainly interacts with RNA via its second and third RNA recognition motifs (RRMs), with specificity for U-rich sequences directed by RRM2. It has recently been shown that RRM3 also contributes to binding, with preferential binding for C-rich sequences. Here we designed UC-rich and CU-rich 10-nt sequences for engagement of both RRM2 and RRM3 and demonstrated that the TIA-1 RRM23 construct preferentially binds the UC-rich RNA ligand (5΄-UUUUUACUCC-3΄). Interestingly, this binding depends on the presence of Lys274 that is C-terminal to RRM3 and binding to equivalent DNA sequences occurs with similar affinity. Small-angle X-ray scattering was used to demonstrate that, upon complex formation with target RNA or DNA, TIA-1 RRM23 adopts a compact structure, showing that both RRMs engage with the target 10-nt sequences to form the complex. We also report the crystal structure of TIA-1 RRM2 in complex with DNA to 2.3 Šresolution providing the first atomic resolution structure of any TIA protein RRM in complex with oligonucleotide. Together our data support a specific mode of TIA-1 RRM23 interaction with target oligonucleotides consistent with the role of TIA-1 in binding RNA to regulate gene expression.
[Mh] Termos MeSH primário: Proteínas de Ligação a DNA/química
DNA/química
Proteínas de Ligação a Poli(A)/química
Ribonucleosídeo Difosfato Redutase/química
[Mh] Termos MeSH secundário: Cristalografia por Raios X
DNA/genética
Proteínas de Ligação a DNA/genética
Regulação da Expressão Gênica
Seres Humanos
Oligonucleotídeos/química
Proteínas de Ligação a Poli(A)/genética
Ligação Proteica/genética
Mapas de Interação de Proteínas/genética
Motivo de Reconhecimento de RNA/genética
Ribonucleosídeo Difosfato Redutase/genética
Antígeno-1 Intracelular de Células T
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (Oligonucleotides); 0 (Poly(A)-Binding Proteins); 0 (T-Cell Intracellular Antigen-1); 0 (TIA1 protein, human); 9007-49-2 (DNA); EC 1.17.4.- (ribonucleotide reductase M2); EC 1.17.4.1 (Ribonucleoside Diphosphate Reductase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170211
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx102


  6 / 17 MEDLINE  
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[PMID]:28115633
[Au] Autor:Samatanga B; Andreou AZ; Klostermeier D
[Ad] Endereço:Institute for Physical Chemistry, University of Muenster, Correnstrasse 30, 48149 Muenster, Germany.
[Ti] Título:Allosteric regulation of helicase core activities of the DEAD-box helicase YxiN by RNA binding to its RNA recognition motif.
[So] Source:Nucleic Acids Res;45(4):1994-2006, 2017 Feb 28.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:DEAD-box proteins share a structurally similar core of two RecA-like domains (RecA_N and RecA_C) that contain the conserved motifs for ATP-dependent RNA unwinding. In many DEAD-box proteins the helicase core is flanked by ancillary domains. To understand the regulation of the DEAD-box helicase YxiN by its C-terminal RNA recognition motif (RRM), we investigated the effect of RNA binding to the RRM on its position relative to the core, and on core activities. RRM/RNA complex formation substantially shifts the RRM from a position close to the RecA_C to the proximity of RecA_N, independent of RNA contacts with the core. RNA binding to the RRM is communicated to the core, and stimulates ATP hydrolysis and RNA unwinding. The conformational space of the core depends on the identity of the RRM-bound RNA. Allosteric regulation of core activities by RNA-induced movement of ancillary domains may constitute a general regulatory mechanism of DEAD-box protein activity.
[Mh] Termos MeSH primário: Sítios de Ligação
RNA Helicases DEAD-box/química
RNA Helicases DEAD-box/metabolismo
Motivo de Reconhecimento de RNA
RNA/metabolismo
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo
Regulação Alostérica
Sequência de Aminoácidos
Hidrólise
Cadeias de Markov
Modelos Moleculares
Conformação Molecular
Conformação de Ácido Nucleico
Peptídeos/química
Peptídeos/metabolismo
Ligação Proteica
RNA/química
RNA/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Peptides); 63231-63-0 (RNA); 8L70Q75FXE (Adenosine Triphosphate); EC 3.6.4.13 (DEAD-box RNA Helicases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170125
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx014


  7 / 17 MEDLINE  
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[PMID]:28077065
[Au] Autor:Liu ZP; Liu S; Chen R; Huang X; Wu LY
[Ad] Endereço:Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, Shandong, 250061, China.
[Ti] Título:Structure alignment-based classification of RNA-binding pockets reveals regional RNA recognition motifs on protein surfaces.
[So] Source:BMC Bioinformatics;18(1):27, 2017 Jan 11.
[Is] ISSN:1471-2105
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Many critical biological processes are strongly related to protein-RNA interactions. Revealing the protein structure motifs for RNA-binding will provide valuable information for deciphering protein-RNA recognition mechanisms and benefit complementary structural design in bioengineering. RNA-binding events often take place at pockets on protein surfaces. The structural classification of local binding pockets determines the major patterns of RNA recognition. RESULTS: In this work, we provide a novel framework for systematically identifying the structure motifs of protein-RNA binding sites in the form of pockets on regional protein surfaces via a structure alignment-based method. We first construct a similarity network of RNA-binding pockets based on a non-sequential-order structure alignment method for local structure alignment. By using network community decomposition, the RNA-binding pockets on protein surfaces are clustered into groups with structural similarity. With a multiple structure alignment strategy, the consensus RNA-binding pockets in each group are identified. The crucial recognition patterns, as well as the protein-RNA binding motifs, are then identified and analyzed. CONCLUSIONS: Large-scale RNA-binding pockets on protein surfaces are grouped by measuring their structural similarities. This similarity network-based framework provides a convenient method for modeling the structural relationships of functional pockets. The local structural patterns identified serve as structure motifs for the recognition with RNA on protein surfaces.
[Mh] Termos MeSH primário: Motivo de Reconhecimento de RNA
Proteínas de Ligação a RNA/química
[Mh] Termos MeSH secundário: Biologia Computacional/métodos
Modelos Moleculares
Conformação Molecular
Proteínas de Ligação a RNA/classificação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA-Binding 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:170113
[St] Status:MEDLINE
[do] DOI:10.1186/s12859-016-1410-1


  8 / 17 MEDLINE  
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[PMID]:27789691
[Au] Autor:Zhang J; Gonzalez LE; Hall TMT
[Ad] Endereço:Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, P.O. Box 12233, MD F3-05, Research Triangle Park, NC 27709, USA.
[Ti] Título:Structural analysis reveals the flexible C-terminus of Nop15 undergoes rearrangement to recognize a pre-ribosomal RNA folding intermediate.
[So] Source:Nucleic Acids Res;45(5):2829-2837, 2017 Mar 17.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The RNA recognition motif (RRM) is the most abundant RNA-binding domain in eukaryotes, and it plays versatile roles in RNA metabolism. Despite its abundance, diversity of RRM structure and function is generated by variations on a conserved core. Yeast Nop15 is an RRM protein that is essential for large ribosomal subunit biogenesis. We determined a 2.0 Å crystal structure of Nop15 that reveals a C-terminal α-helical region obscures its canonical RNA-binding surface. Small-angle X-ray scattering, NMR and RNA-binding analyses further reveal that the C-terminal residues of Nop15 are highly flexible, but essential for tight RNA binding. Moreover, comparison with a recently reported cryo-electron microscopy structure indicates that dramatic rearrangement of the C-terminal region of Nop15 in the pre-ribosome exposes the RNA-binding surface to recognize the base of its stem-loop target RNA and extends a newly-formed α helix to the distal loop where it forms protein interactions.
[Mh] Termos MeSH primário: Dobramento de RNA
RNA Ribossômico/química
Proteínas Ribossômicas/química
Proteínas de Saccharomyces cerevisiae/química
[Mh] Termos MeSH secundário: Sítios de Ligação
Ligação Proteica
Redobramento de Proteína
Precursores de RNA/química
Precursores de RNA/metabolismo
Motivo de Reconhecimento de RNA
RNA Ribossômico/metabolismo
Proteínas Ribossômicas/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Nop15 protein, S cerevisiae); 0 (RNA Precursors); 0 (RNA, Ribosomal); 0 (Ribosomal Proteins); 0 (Saccharomyces cerevisiae Proteins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170808
[Lr] Data última revisão:
170808
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161030
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkw961


  9 / 17 MEDLINE  
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[PMID]:27959512
[Au] Autor:Brown KA; Sharifi S; Hussain R; Donaldson L; Bayfield MA; Wilson DJ
[Ad] Endereço:Department of Chemistry, York University , Toronto, ON M3J 1P3, Canada.
[Ti] Título:Distinct Dynamic Modes Enable the Engagement of Dissimilar Ligands in a Promiscuous Atypical RNA Recognition Motif.
[So] Source:Biochemistry;55(51):7141-7150, 2016 Dec 27.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Conformational dynamics play a critical role in ligand binding, often conferring divergent activities and specificities even in species with highly similar ground-state structures. Here, we employ time-resolved electrospray ionization hydrogen-deuterium exchange (TRESI-HDX) to characterize the changes in dynamics that accompany oligonucleotide binding in the atypical RNA recognition motif (RRM2) in the C-terminal domain (CTD) of human La protein. Using this approach, which is uniquely capable of probing changes in the structure and dynamics of weakly ordered regions of proteins, we reveal that binding of RRM2 to a model 23-mer single-stranded RNA and binding of RRM2 to structured IRES domain IV of the hepatitis C viral (HCV) RNA are driven by fundamentally different dynamic processes. In particular, binding of the single-stranded RNA induces helical "unwinding" in a region of the CTD previously hypothesized to play an important role in La and La-related protein-associated RNA remodeling, while the same region becomes less dynamic upon engagement with the double-stranded HCV RNA. Binding of double-stranded RNA also involves less penetration into the RRM2 binding pocket and more engagement with the unstructured C-terminus of the La CTD. The complementarity between TRESI-HDX and Δδ nuclear magnetic resonance measurements for ligand binding analysis is also explored.
[Mh] Termos MeSH primário: Autoantígenos/química
Motivo de Reconhecimento de RNA
RNA de Cadeia Dupla/química
RNA/química
Ribonucleoproteínas/química
[Mh] Termos MeSH secundário: Autoantígenos/genética
Autoantígenos/metabolismo
Sequência de Bases
Sítios de Ligação/genética
Medição da Troca de Deutério/métodos
Hepatite C/genética
Seres Humanos
Ligantes
Espectroscopia de Ressonância Magnética
Espectrometria de Massas/métodos
Modelos Moleculares
Mutação
Conformação de Ácido Nucleico
Polirribonucleotídeos/química
Polirribonucleotídeos/genética
Polirribonucleotídeos/metabolismo
Ligação Proteica
Conformação Proteica
Domínios Proteicos
RNA/genética
RNA/metabolismo
RNA de Cadeia Dupla/genética
RNA de Cadeia Dupla/metabolismo
RNA Viral/química
RNA Viral/genética
RNA Viral/metabolismo
Ribonucleoproteínas/genética
Ribonucleoproteínas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Autoantigens); 0 (Ligands); 0 (Polyribonucleotides); 0 (RNA, Double-Stranded); 0 (RNA, Viral); 0 (Ribonucleoproteins); 0 (SS-B antigen); 63231-63-0 (RNA)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170530
[Lr] Data última revisão:
170530
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161214
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.6b00995


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[PMID]:27428511
[Au] Autor:Chen Y; Yang F; Zubovic L; Pavelitz T; Yang W; Godin K; Walker M; Zheng S; Macchi P; Varani G
[Ad] Endereço:Department of Chemistry, University of Washington, Seattle, Washington, USA.
[Ti] Título:Targeted inhibition of oncogenic miR-21 maturation with designed RNA-binding proteins.
[So] Source:Nat Chem Biol;12(9):717-23, 2016 Sep.
[Is] ISSN:1552-4469
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The RNA recognition motif (RRM) is the largest family of eukaryotic RNA-binding proteins. Engineered RRMs with well-defined specificity would provide valuable tools and an exacting test of the current understanding of specificity. We have redesigned the specificity of an RRM using rational methods and demonstrated retargeting of its activity in cells. We engineered the conserved RRM of human Rbfox proteins to specifically bind to the terminal loop of a microRNA precursor (pre-miR-21) with high affinity and inhibit its processing by Drosha and Dicer. We further engineered Giardia Dicer by replacing its PAZ domain with the designed RRM. The reprogrammed enzyme degrades pre-miR-21 specifically in vitro and suppresses mature miR-21 levels in cells, which results in increased expression of the tumor suppressor PDCD4 and significantly decreased viability for cancer cells. The results demonstrate the feasibility of rationally engineering the sequence-specificity of RRMs and of using this ubiquitous platform for diverse biological applications.
[Mh] Termos MeSH primário: MicroRNAs/biossíntese
Proteínas de Ligação a RNA/metabolismo
Proteínas de Ligação a RNA/farmacologia
[Mh] Termos MeSH secundário: Seres Humanos
MicroRNAs/genética
MicroRNAs/metabolismo
Modelos Moleculares
Engenharia de Proteínas
Motivo de Reconhecimento de RNA
Proteínas de Ligação a RNA/síntese química
Proteínas de Ligação a RNA/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MIRN21 microRNA, human); 0 (MicroRNAs); 0 (RNA-Binding Proteins)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170515
[Lr] Data última revisão:
170515
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160719
[St] Status:MEDLINE
[do] DOI:10.1038/nchembio.2128



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