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Pesquisa : G02.111.570.060.720 [Categoria DeCS]
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[PMID]:28986260
[Au] Autor:Dicke SS; Tatge L; Engen PE; Culp M; Masterson LR
[Ad] Endereço:Department of Chemistry, Hamline University, St. Paul, MN 55104, United States.
[Ti] Título:Isothermal titration calorimetry and vesicle leakage assays highlight the differential behaviors of tau repeat segments upon interaction with anionic lipid membranes.
[So] Source:Biochem Biophys Res Commun;493(4):1504-1509, 2017 Dec 02.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Tau misfolding has been implicated in a variety of tauopathies, including Alzheimer's disease. The microtubule binding domain of tau consists of four repeat segments (R1-R4), and aggregation of these segments leads to the formation of neurofibrillary tangles. Previous studies indicate that misfolded tau associates with anionic phospholipid membranes, invoking structural transformations that could play a role in aggregation. Here, we investigated the role of membrane surface charge on the binding affinity of individual tau repeat segments, and whether these segments exhibit lytic activity. We quantified the thermodynamics of this process in terms of the affinity (K ), enthalpy (ΔH), entropy (ΔS), and change in specific heat capacity (ΔC ). While neutral membranes exhibited weak interactions with each tau repeat segment, segments R2 and R3 exhibited relatively strong binding with anionic membranes with favorable ΔS and a negative value of ΔC . Calcein leakage assays show that each repeat segment displays lytic activity, but only upon the interaction with anionic membranes. Taken together, these results distinguish the relative selectivity for anionic membranes by each repeat segment and the degree of membrane disruption that results.
[Mh] Termos MeSH primário: Proteínas tau/química
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Calorimetria/métodos
Seres Humanos
Lipídeos de Membrana/química
Lipídeos de Membrana/metabolismo
Agregação Patológica de Proteínas
Dobramento de Proteína
Domínios e Motivos de Interação entre Proteínas
Sequências Repetitivas de Aminoácidos
Tauopatias/etiologia
Tauopatias/genética
Tauopatias/metabolismo
Termodinâmica
Proteínas tau/genética
Proteínas tau/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MAPT protein, human); 0 (Membrane Lipids); 0 (tau Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171008
[St] Status:MEDLINE


  2 / 2436 MEDLINE  
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[PMID]:28939751
[Au] Autor:Bakker H; Gerardy-Schahn R
[Ad] Endereço:From the Institute of Clinical Biochemistry, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
[Ti] Título:A sweet development in Notch regulation.
[So] Source:J Biol Chem;292(38):15974-15975, 2017 Sep 22.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The transmembrane signaling protein Notch, which is crucial for embryonic cell fate decisions, has 36 extracellular EGF domains that are glycosylated in variable and complex ways. A new study shows that -fucose and -glucose stabilize the repeats but that extension of glucose by xylose weakens stability, explained by the binding of the glycan to a protein groove. This work shows how different types of glycosylation can distinctly influence protein stability and structure.
[Mh] Termos MeSH primário: Receptores Notch/química
Receptores Notch/metabolismo
[Mh] Termos MeSH secundário: Glicosilação
Modelos Moleculares
Conformação Proteica
Estabilidade Proteica
Sequências Repetitivas de Aminoácidos
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptors, Notch)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170924
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.H117.800102


  3 / 2436 MEDLINE  
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[PMID]:28873984
[Au] Autor:Klinger M
[Ad] Endereço:Hawk BioDiscovery, 7465 Highway 51, Sterrett, AL 35147, USA.
[Ti] Título:A role for macromolecular crowding in off-target binding of therapeutic antibodies.
[So] Source:Protein Eng Des Sel;30(7):489-494, 2017 Jul 01.
[Is] ISSN:1741-0134
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The nonspecific binding of certain therapeutic antibodies to tissues or to soluble biomolecules can accelerate their clearance from the circulation and undermine their benefit to patients. This article proposes that tandem amino acid repeat sequences in antibody hypervariable segments, particularly the complementarity determining regions (CDRs), can enhance this off-target binding. This hypothesis is based on two sets of observations. First, in a limited number of cases, antibodies with clusters of amino acid repeats in their CDRs have significantly higher clearance rates in experimental animals than otherwise identical antibodies without the repeats. Second, tandem amino acid repeats are abundant in intracellular hub proteins where they appear to promote the promiscuous binding of these proteins to a wide variety of other molecules. These nonspecific hub protein interactions are highly favored by the intense macromolecular crowding that permeates the cytoplasm. A survey of the variable region sequences of 137 antibodies in various stages of development revealed that 26 have at least one CDR containing a cluster of three closely spaced amino acid repeats. If the overall hypothesis is valid, then it suggests strategies for site-directed mutagenesis to improve pharmacokinetic behavior and for the design of more reliable in vitro binding assays to predict off-target binding in vivo.
[Mh] Termos MeSH primário: Anticorpos/química
Regiões Determinantes de Complementaridade/genética
Ligação Proteica/genética
Sequências Repetitivas de Aminoácidos/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Anticorpos/genética
Anticorpos/uso terapêutico
Afinidade de Anticorpos/genética
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies); 0 (Complementarity Determining Regions)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170907
[St] Status:MEDLINE
[do] DOI:10.1093/protein/gzx035


  4 / 2436 MEDLINE  
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[PMID]:28864774
[Au] Autor:Bourdin B; Briot J; Tétreault MP; Sauvé R; Parent L
[Ad] Endereço:Centre de Recherche de l'Institut de Cardiologie de Montréal, Université de Montréal, Montréal, Québec H3C 3J7, Canada.
[Ti] Título:Negatively charged residues in the first extracellular loop of the L-type Ca 1.2 channel anchor the interaction with the Ca α2δ1 auxiliary subunit.
[So] Source:J Biol Chem;292(42):17236-17249, 2017 Oct 20.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Voltage-gated L-type Ca 1.2 channels in cardiomyocytes exist as heteromeric complexes. Co-expression of Ca α2δ1 with Ca ß/Ca α1 proteins reconstitutes the functional properties of native L-type currents, but the interacting domains at the Ca 1.2/Ca α2δ1 interface are unknown. Here, a homology-based model of Ca 1.2 identified protein interfaces between the extracellular domain of Ca α2δ1 and the extracellular loops of the Ca α1 protein in repeats I (IS1S2 and IS5S6), II (IIS5S6), and III (IIIS5S6). Insertion of a 9-residue hemagglutinin epitope in IS1S2, but not in IS5S6 or in IIS5S6, prevented the co-immunoprecipitation of Ca 1.2 with Ca α2δ1. IS1S2 contains a cluster of three conserved negatively charged residues Glu-179, Asp-180, and Asp-181 that could contribute to non-bonded interactions with Ca α2δ1. Substitutions of Ca 1.2 Asp-181 impaired the co-immunoprecipitation of Ca ß/Ca 1.2 with Ca α2δ1 and the Ca α2δ1-dependent shift in voltage-dependent activation gating. In contrast, single substitutions in Ca 1.2 in neighboring positions in the same loop (179, 180, and 182-184) did not significantly alter the functional up-regulation of Ca 1.2 whole-cell currents. However, a negatively charged residue at position 180 was necessary to convey the Ca α2δ1-mediated shift in the activation gating. We also found a more modest contribution from the positively charged Arg-1119 in the extracellular pore region in repeat III of Ca 1.2. We conclude that Ca 1.2 Asp-181 anchors the physical interaction that facilitates the Ca α2δ1-mediated functional modulation of Ca 1.2 currents. By stabilizing the first extracellular loop of Ca 1.2, Ca α2δ1 may up-regulate currents by promoting conformations of the voltage sensor that are associated with the channel's open state.
[Mh] Termos MeSH primário: Canais de Cálcio Tipo L/química
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Canais de Cálcio Tipo L/genética
Canais de Cálcio Tipo L/metabolismo
Linhagem Celular
Ativação do Canal Iônico/fisiologia
Mutação de Sentido Incorreto
Miócitos Cardíacos/metabolismo
Estrutura Secundária de Proteína
Coelhos
Ratos
Sequências Repetitivas de Aminoácidos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channels, L-Type); 0 (L-type calcium channel alpha(1C))
[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:170903
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.806893


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[PMID]:28805808
[Au] Autor:Chavali S; Chavali PL; Chalancon G; de Groot NS; Gemayel R; Latysheva NS; Ing-Simmons E; Verstrepen KJ; Balaji S; Babu MM
[Ad] Endereço:MRC Laboratory of Molecular Biology, Cambridge, UK.
[Ti] Título:Constraints and consequences of the emergence of amino acid repeats in eukaryotic proteins.
[So] Source:Nat Struct Mol Biol;24(9):765-777, 2017 Sep.
[Is] ISSN:1545-9985
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Proteins with amino acid homorepeats have the potential to be detrimental to cells and are often associated with human diseases. Why, then, are homorepeats prevalent in eukaryotic proteomes? In yeast, homorepeats are enriched in proteins that are essential and pleiotropic and that buffer environmental insults. The presence of homorepeats increases the functional versatility of proteins by mediating protein interactions and facilitating spatial organization in a repeat-dependent manner. During evolution, homorepeats are preferentially retained in proteins with stringent proteostasis, which might minimize repeat-associated detrimental effects such as unregulated phase separation and protein aggregation. Their presence facilitates rapid protein divergence through accumulation of amino acid substitutions, which often affect linear motifs and post-translational-modification sites. These substitutions may result in rewiring protein interaction and signaling networks. Thus, homorepeats are distinct modules that are often retained in stringently regulated proteins. Their presence facilitates rapid exploration of the genotype-phenotype landscape of a population, thereby contributing to adaptation and fitness.
[Mh] Termos MeSH primário: Proteínas/genética
Proteínas/metabolismo
Sequências Repetitivas de Aminoácidos/genética
[Mh] Termos MeSH secundário: Evolução Biológica
Eucariotos
Mapas de Interação de Proteínas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Proteins)
[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:170815
[St] Status:MEDLINE
[do] DOI:10.1038/nsmb.3441


  6 / 2436 MEDLINE  
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[PMID]:28729422
[Au] Autor:Takeuchi H; Yu H; Hao H; Takeuchi M; Ito A; Li H; Haltiwanger RS
[Ad] Endereço:From the Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602.
[Ti] Título:-Glycosylation modulates the stability of epidermal growth factor-like repeats and thereby regulates Notch trafficking.
[So] Source:J Biol Chem;292(38):15964-15973, 2017 Sep 22.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Glycosylation in the endoplasmic reticulum (ER) is closely associated with protein folding and quality control. We recently described a non-canonical ER quality control mechanism for folding of thrombospondin type 1 repeats by protein -fucosyltransferase 2 (POFUT2). Epidermal growth factor-like (EGF) repeats are also small cysteine-rich protein motifs that can be -glycosylated by several ER-localized enzymes, including protein -glucosyltransferase 1 (POGLUT1) and POFUT1. Both POGLUT1 and POFUT1 modify the Notch receptor on multiple EGF repeats and are essential for full Notch function. The fact that POGLUT1 and POFUT1 can distinguish between folded and unfolded EGF repeats raised the possibility that they participate in a quality control pathway for folding of EGF repeats in proteins such as Notch. Here, we demonstrate that cell-surface expression of endogenous Notch1 in HEK293T cells is dependent on the presence of and in an additive manner. unfolding assays reveal that addition of -glucose or -fucose stabilizes a single EGF repeat and that addition of both -glucose and -fucose enhances stability in an additive manner. Finally, we solved the crystal structure of a single EGF repeat covalently modified by a full -glucose trisaccharide at 2.2 Å resolution. The structure reveals that the glycan fills up a surface groove of the EGF with multiple contacts with the protein, providing a chemical basis for the stabilizing effects of the glycans. Taken together, this work suggests that -fucose and -glucose glycans cooperatively stabilize individual EGF repeats through intramolecular interactions, thereby regulating Notch trafficking in cells.
[Mh] Termos MeSH primário: Fator de Crescimento Epidérmico/química
Oxigênio/metabolismo
Receptores Notch/química
Receptores Notch/metabolismo
Sequências Repetitivas de Aminoácidos
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Fucosiltransferases/deficiência
Fucosiltransferases/genética
Regulação da Expressão Gênica
Técnicas de Inativação de Genes
Glucose/metabolismo
Glucosiltransferases/deficiência
Glucosiltransferases/genética
Glicosilação
Células HEK293
Seres Humanos
Camundongos
Modelos Moleculares
Conformação Proteica
Transporte Proteico
Receptor Notch1/química
Receptor Notch1/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Receptor, Notch1); 0 (Receptors, Notch); 62229-50-9 (Epidermal Growth Factor); EC 2.4.1.- (Fucosyltransferases); EC 2.4.1.- (Glucosyltransferases); EC 2.4.1.- (POGLUT1 protein, human); EC 2.4.1.221 (polypeptide fucosyltransferase); IY9XDZ35W2 (Glucose); S88TT14065 (Oxygen)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170722
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.800102


  7 / 2436 MEDLINE  
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[PMID]:28705932
[Au] Autor:Kroh HK; Chandrasekaran R; Rosenthal K; Woods R; Jin X; Ohi MD; Nyborg AC; Rainey GJ; Warrener P; Spiller BW; Lacy DB
[Ad] Endereço:From the Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2363.
[Ti] Título:Use of a neutralizing antibody helps identify structural features critical for binding of toxin TcdA to the host cell surface.
[So] Source:J Biol Chem;292(35):14401-14412, 2017 Sep 01.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:is a clinically significant pathogen that causes mild-to-severe (and often recurrent) colon infections. Disease symptoms stem from the activities of two large, multidomain toxins known as TcdA and TcdB. The toxins can bind, enter, and perturb host cell function through a multistep mechanism of receptor binding, endocytosis, pore formation, autoproteolysis, and glucosyltransferase-mediated modification of host substrates. Monoclonal antibodies that neutralize toxin activity provide a survival benefit in preclinical animal models and prevent recurrent infections in human clinical trials. However, the molecular mechanisms involved in these neutralizing activities are unclear. To this end, we performed structural studies on a neutralizing monoclonal antibody, PA50, a humanized mAb with both potent and broad-spectrum neutralizing activity, in complex with TcdA. Electron microscopy imaging and multiangle light-scattering analysis revealed that PA50 binds multiple sites on the TcdA C-terminal combined repetitive oligopeptides (CROPs) domain. A crystal structure of two PA50 Fabs bound to a segment of the TcdA CROPs helped define a conserved epitope that is distinct from previously identified carbohydrate-binding sites. Binding of TcdA to the host cell surface was directly blocked by either PA50 mAb or Fab and suggested that receptor blockade is the mechanism by which PA50 neutralizes TcdA. These findings highlight the importance of the CROPs C terminus in cell-surface binding and a role for neutralizing antibodies in defining structural features critical to a pathogen's mechanism of action. We conclude that PA50 protects host cells by blocking the binding of TcdA to cell surfaces.
[Mh] Termos MeSH primário: Antibacterianos/metabolismo
Anticorpos Neutralizantes/metabolismo
Toxinas Bacterianas/metabolismo
Clostridium difficile/enzimologia
Enterócitos/metabolismo
Enterotoxinas/metabolismo
Glucosiltransferases/metabolismo
Modelos Moleculares
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Antibacterianos/química
Anticorpos Monoclonais Humanizados/química
Anticorpos Monoclonais Humanizados/metabolismo
Anticorpos Neutralizantes/química
Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Proteínas de Bactérias/toxicidade
Toxinas Bacterianas/química
Toxinas Bacterianas/genética
Toxinas Bacterianas/toxicidade
Sítios de Ligação de Anticorpos
Células CACO-2
Sequência Conservada
Cristalografia por Raios X
Enterócitos/efeitos dos fármacos
Enterotoxinas/química
Enterotoxinas/genética
Enterotoxinas/toxicidade
Mapeamento de Epitopos
Glucosiltransferases/química
Glucosiltransferases/genética
Glucosiltransferases/toxicidade
Seres Humanos
Fragmentos Fab das Imunoglobulinas/química
Fragmentos Fab das Imunoglobulinas/metabolismo
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Fragmentos de Peptídeos/toxicidade
Conformação Proteica
Domínios e Motivos de Interação entre Proteínas
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Proteínas Recombinantes/toxicidade
Sequências Repetitivas de Aminoácidos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Antibodies, Monoclonal, Humanized); 0 (Antibodies, Neutralizing); 0 (Bacterial Proteins); 0 (Bacterial Toxins); 0 (Enterotoxins); 0 (Immunoglobulin Fab Fragments); 0 (Peptide Fragments); 0 (Recombinant Proteins); 0 (tcdA protein, Clostridium difficile); EC 2.4.1.- (Glucosyltransferases)
[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:170715
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.781112


  8 / 2436 MEDLINE  
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[PMID]:28630045
[Au] Autor:Shimizu H; Toma-Fukai S; Saijo S; Shimizu N; Kontani K; Katada T; Shimizu T
[Ad] Endereço:From the Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
[Ti] Título:Structure-based analysis of the guanine nucleotide exchange factor SmgGDS reveals armadillo-repeat motifs and key regions for activity and GTPase binding.
[So] Source:J Biol Chem;292(32):13441-13448, 2017 Aug 11.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Small GTPases are molecular switches that have critical biological roles and are controlled by GTPase-activating proteins and guanine nucleotide exchange factors (GEFs). The smg GDP dissociation stimulator (SmgGDS) protein functions as a GEF for the RhoA and RhoC small GTPases. SmgGDS has various regulatory roles, including small GTPase trafficking and localization and as a molecular chaperone, and interacts with many small GTPases possessing polybasic regions. Two SmgGDS splice variants, SmgGDS-558 and SmgGDS-607, differ in GEF activity and binding affinity for RhoA depending on the lipidation state, but the reasons for these differences are unclear. Here we determined the crystal structure of SmgGDS-558, revealing a fold containing tandem copies of armadillo repeats not present in other GEFs. We also observed that SmgGDS harbors distinct positively and negatively charged regions, both of which play critical roles in binding to RhoA and GEF activity. This is the first report demonstrating a relationship between the molecular function and atomic structure of SmgGDS. Our findings indicate that the two SmgGDS isoforms differ in GTPase binding and GEF activity, depending on the lipidation state, thus providing useful information about the cellular functions of SmgGDS in cells.
[Mh] Termos MeSH primário: Fatores de Troca do Nucleotídeo Guanina/metabolismo
Modelos Moleculares
Prenilação de Proteína
Proteína rhoA de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Motivos de Aminoácidos
Substituição de Aminoácidos
Sítios de Ligação
Farnesiltranstransferase/genética
Farnesiltranstransferase/metabolismo
Fatores de Troca do Nucleotídeo Guanina/química
Fatores de Troca do Nucleotídeo Guanina/genética
Seres Humanos
Cinética
Simulação de Acoplamento Molecular
Mutagênese Sítio-Dirigida
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Mutação Puntual
Isoformas de Proteínas/química
Isoformas de Proteínas/genética
Isoformas de Proteínas/metabolismo
Multimerização Proteica
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Sequências Repetitivas de Aminoácidos
Solubilidade
Ressonância de Plasmônio de Superfície
Proteína rhoA de Ligação ao GTP/química
Proteína rhoA de Ligação ao GTP/genética
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Guanine Nucleotide Exchange Factors); 0 (Peptide Fragments); 0 (Protein Isoforms); 0 (RAP1GDS1 protein, human); 0 (Recombinant Fusion Proteins); 0 (Recombinant Proteins); 124671-05-2 (RHOA protein, human); EC 2.5.1.29 (Farnesyltranstransferase); EC 3.6.5.2 (rhoA GTP-Binding Protein)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170825
[Lr] Data última revisão:
170825
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170621
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.792556


  9 / 2436 MEDLINE  
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[PMID]:28617812
[Au] Autor:Espada R; Parra RG; Mora T; Walczak AM; Ferreiro DU
[Ad] Endereço:Protein Physiology Lab, Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica. Buenos Aires, Argentina. / CONICET - Universidad de Buenos Aires. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN). Buenos Aires,
[Ti] Título:Inferring repeat-protein energetics from evolutionary information.
[So] Source:PLoS Comput Biol;13(6):e1005584, 2017 Jun.
[Is] ISSN:1553-7358
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Natural protein sequences contain a record of their history. A common constraint in a given protein family is the ability to fold to specific structures, and it has been shown possible to infer the main native ensemble by analyzing covariations in extant sequences. Still, many natural proteins that fold into the same structural topology show different stabilization energies, and these are often related to their physiological behavior. We propose a description for the energetic variation given by sequence modifications in repeat proteins, systems for which the overall problem is simplified by their inherent symmetry. We explicitly account for single amino acid and pair-wise interactions and treat higher order correlations with a single term. We show that the resulting evolutionary field can be interpreted with structural detail. We trace the variations in the energetic scores of natural proteins and relate them to their experimental characterization. The resulting energetic evolutionary field allows the prediction of the folding free energy change for several mutants, and can be used to generate synthetic sequences that are statistically indistinguishable from the natural counterparts.
[Mh] Termos MeSH primário: Evolução Química
Modelos Moleculares
Proteínas/química
Proteínas/ultraestrutura
Sequências Repetitivas de Aminoácidos/genética
Análise de Sequência de Proteína/métodos
[Mh] Termos MeSH secundário: Transferência de Energia
Modelos Químicos
Mutação Puntual/genética
Conformação Proteica
Dobramento de Proteína
Proteínas/genética
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (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:170616
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pcbi.1005584


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[PMID]:28536263
[Au] Autor:Zempel H; Dennissen FJA; Kumar Y; Luedtke J; Biernat J; Mandelkow EM; Mandelkow E
[Ad] Endereço:From the German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany, hans.zempel@dzne.de hanszempel@hotmail.com.
[Ti] Título:Axodendritic sorting and pathological missorting of Tau are isoform-specific and determined by axon initial segment architecture.
[So] Source:J Biol Chem;292(29):12192-12207, 2017 Jul 21.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Subcellular mislocalization of the microtubule-associated protein Tau is a hallmark of Alzheimer disease (AD) and other tauopathies. Six Tau isoforms, differentiated by the presence or absence of a second repeat or of N-terminal inserts, exist in the human CNS, but their physiological and pathological differences have long remained elusive. Here, we investigated the properties and distributions of human and rodent Tau isoforms in primary forebrain rodent neurons. We found that the Tau diffusion barrier (TDB), located within the axon initial segment (AIS), controls retrograde (axon-to-soma) and anterograde (soma-to-axon) traffic of Tau. Tau isoforms without the N-terminal inserts were sorted efficiently into the axon. However, the longest isoform (2N4R-Tau) was partially retained in cell bodies and dendrites, where it accelerated spine and dendrite growth. The TDB (located within the AIS) was impaired when AIS components (ankyrin G, EB1) were knocked down or when glycogen synthase kinase-3ß (GSK3ß; an AD-associated kinase tethered to the AIS) was overexpressed. Using superresolution nanoscopy and live-cell imaging, we observed that microtubules within the AIS appeared highly dynamic, a feature essential for the TDB. Pathomechanistically, amyloid-ß insult caused cofilin activation and F-actin remodeling and decreased microtubule dynamics in the AIS. Concomitantly with these amyloid-ß-induced disruptions, the AIS/TDB sorting function failed, causing AD-like Tau missorting. In summary, we provide evidence that the human and rodent Tau isoforms differ in axodendritic sorting and amyloid-ß-induced missorting and that the axodendritic distribution of Tau depends on AIS integrity.
[Mh] Termos MeSH primário: Segmento Inicial do Axônio/metabolismo
Córtex Cerebral/metabolismo
Dendritos/metabolismo
Microtúbulos/metabolismo
Neurônios/metabolismo
Proteínas tau/metabolismo
[Mh] Termos MeSH secundário: Doença de Alzheimer/metabolismo
Doença de Alzheimer/patologia
Animais
Segmento Inicial do Axônio/patologia
Células Cultivadas
Córtex Cerebral/citologia
Córtex Cerebral/patologia
Dendritos/patologia
Difusão
Embrião de Mamíferos/citologia
Deleção de Genes
Seres Humanos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Microtúbulos/patologia
Mutagênese Insercional
Neurônios/citologia
Neurônios/patologia
Domínios e Motivos de Interação entre Proteínas
Isoformas de Proteínas/antagonistas & inibidores
Isoformas de Proteínas/química
Isoformas de Proteínas/genética
Isoformas de Proteínas/metabolismo
Transporte Proteico
Interferência de RNA
Ratos Wistar
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/metabolismo
Sequências Repetitivas de Aminoácidos
Proteínas tau/antagonistas & inibidores
Proteínas tau/química
Proteínas tau/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MAPT protein, human); 0 (Mapt protein, mouse); 0 (Protein Isoforms); 0 (Recombinant Fusion Proteins); 0 (tau 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:170525
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.784702



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