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[PMID]:29306024
[Au] Autor:Hill KL; Hamers T; Kamstra JH; Willmore WG; Letcher RJ
[Ad] Endereço:Ecotoxicology and Wildlife Health Division, Environment and Climate Change Canada, National Wildlife Research Centre, Carleton University, Ottawa, Canada; Department of Biology, Carleton University, Ottawa, Canada; Intrinsik Corp., Ottawa, Canada.
[Ti] Título:Organophosphate triesters and selected metabolites enhance binding of thyroxine to human transthyretin in vitro.
[So] Source:Toxicol Lett;285:87-93, 2018 Mar 15.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The toxicological properties of organophosphate (OP) triesters that are used as flame retardants and plasticizers are currently not well understood, though increasing evidence suggests they can affect the thyroid system. Perturbation of thyroid hormone (TH) transport is one mechanism of action that may affect thyroid function. The present study applied an in vitro competitive protein binding assay with thyroxine (T4) and human transthyretin (hTTR) transport protein to determine the potential for the OP triesters, TDCIPP (tris(1,3-dichloro-2-propyl) phosphate), TBOEP (tris(butoxyethyl) phosphate), TEP (triethyl phosphate), TPHP (triphenyl phosphate), p-OH-TPHP (para-hydroxy triphenyl phosphate), and the OP diester DPHP (diphenyl phosphate), to competitively displace T4 from hTTR. Enhancement of T4 binding to hTTR, rather than the hypothesized competition, was observed for the six OP esters and in a concentration-dependent manner. For example, T4-hTTR binding was significantly increased at concentrations of TBOEP as low as 64 nM, and up to 184% of controls at 5000 nM. A plausible explanation of these results, which to our knowledge has not been previously reported, may be allosteric interactions of the OP esters with hTTR allowing T4 to access the second site of the TH binding pocket. These in vitro results suggest a novel mechanism of OP ester toxicity via T4 binding enhancement, and possible dysregulation of T4-hTTR interactions.
[Mh] Termos MeSH primário: Retardadores de Chama/toxicidade
Organofosfatos/toxicidade
Plastificantes/toxicidade
Pré-Albumina/metabolismo
Tiroxina/metabolismo
[Mh] Termos MeSH secundário: Ligação Competitiva
Ésteres
Retardadores de Chama/metabolismo
Seres Humanos
Organofosfatos/metabolismo
Plastificantes/metabolismo
Ligação Proteica
Glândula Tireoide/efeitos dos fármacos
Glândula Tireoide/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Esters); 0 (Flame Retardants); 0 (Organophosphates); 0 (Plasticizers); 0 (Prealbumin); Q51BO43MG4 (Thyroxine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180219
[Lr] Data última revisão:
180219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180107
[St] Status:MEDLINE


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[PMID]:29240759
[Au] Autor:Zanotti G; Vallese F; Ferrari A; Menozzi I; Saldaño TE; Berto P; Fernandez-Alberti S; Berni R
[Ad] Endereço:Department of Biomedical Sciences, University of Padua, Padua, Italy.
[Ti] Título:Structural and dynamics evidence for scaffold asymmetric flexibility of the human transthyretin tetramer.
[So] Source:PLoS One;12(12):e0187716, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The molecular symmetry of multimeric proteins is generally determined by using X-ray diffraction techniques, so that the basic question as to whether this symmetry is perfectly preserved for the same protein in solution remains open. In this work, human transthyretin (TTR), a homotetrameric plasma transport protein with two binding sites for the thyroid hormone thyroxine (T4), is considered as a case study. Based on the crystal structure of the TTR tetramer, a hypothetical D2 symmetry is inferred for the protein in solution, whose functional behavior reveals the presence of two markedly different Kd values for the two T4 binding sites. The latter property has been ascribed to an as yet uncharacterized negative binding cooperativity. A triple mutant form of human TTR (F87M/L110M/S117E TTR), which is monomeric in solution, crystallizes as a tetrameric protein and its structure has been determined. The exam of this and several other crystal forms of human TTR suggests that the TTR scaffold possesses a significant structural flexibility. In addition, TTR tetramer dynamics simulated using normal modes analysis exposes asymmetric vibrational patterns on both dimers and thermal fluctuations reveal small differences in size and flexibility for ligand cavities at each dimer-dimer interface. Such small structural differences between monomers can lead to significant functional differences on the TTR tetramer dynamics, a feature that may explain the functional heterogeneity of the T4 binding sites, which is partially overshadowed by the crystal state.
[Mh] Termos MeSH primário: Biopolímeros/química
Pré-Albumina/química
[Mh] Termos MeSH secundário: Cristalografia por Raios X
Seres Humanos
Conformação Proteica
Proteínas Recombinantes/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biopolymers); 0 (Prealbumin); 0 (Recombinant Proteins)
[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:171215
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0187716


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[PMID]:28985740
[Au] Autor:Guttenplan APM; Young LJ; Matak-Vinkovic D; Kaminski CF; Knowles TPJ; Itzhaki LS
[Ad] Endereço:Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK.
[Ti] Título:Nanoscale click-reactive scaffolds from peptide self-assembly.
[So] Source:J Nanobiotechnology;15(1):70, 2017 Oct 06.
[Is] ISSN:1477-3155
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Due to their natural tendency to self-assemble, proteins and peptides are important components for organic nanotechnology. One particular class of peptides of recent interest is those that form amyloid fibrils, as this self-assembly results in extremely strong, stable quasi-one-dimensional structures which can be used to organise a wide range of cargo species including proteins and oligonucleotides. However, assembly of peptides already conjugated to proteins is limited to cargo species that do not interfere sterically with the assembly process or misfold under the harsh conditions often used for assembly. Therefore, a general method is needed to conjugate proteins and other molecules to amyloid fibrils after the fibrils have self-assembled. RESULTS: Here we have designed an amyloidogenic peptide based on the TTR105-115 fragment of transthyretin to form fibrils that display an alkyne functionality, important for bioorthogonal chemical reactions, on their surface. The fibrils were formed and reacted both with an azide-containing amino acid and with an azide-functionalised dye by the Huisgen cycloaddition, one of the class of "click" reactions. Mass spectrometry and total internal reflection fluorescence optical microscopy were used to show that peptides incorporated into the fibrils reacted with the azide while maintaining the structure of the fibril. These click-functionalised amyloid fibrils have a variety of potential uses in materials and as scaffolds for bionanotechnology. DISCUSSION: Although previous studies have produced peptides that can both form amyloid fibrils and undergo "click"-type reactions, this is the first example of amyloid fibrils that can undergo such a reaction after they have been formed. Our approach has the advantage that self-assembly takes place before click functionalization rather than pre-functionalised building blocks self-assembling. Therefore, the molecules used to functionalise the fibril do not themselves have to be exposed to harsh, amyloid-forming conditions. This means that a wider range of proteins can be used as ligands in this process. For instance, the fibrils can be functionalised with a green fluorescent protein that retains its fluorescence after it is attached to the fibrils, whereas this protein loses its fluorescence if it is exposed to the conditions used for aggregation.
[Mh] Termos MeSH primário: Alquinos/química
Amiloide/química
Azidas/química
Química Click/métodos
Peptídeos/química
Pré-Albumina/química
[Mh] Termos MeSH secundário: Alquinos/síntese química
Sequência de Aminoácidos
Amiloide/síntese química
Azidas/síntese química
Proteínas de Fluorescência Verde/síntese química
Proteínas de Fluorescência Verde/química
Nanotecnologia
Peptídeos/síntese química
Pré-Albumina/síntese química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Alkynes); 0 (Amyloid); 0 (Azides); 0 (Peptides); 0 (Prealbumin); 147336-22-9 (Green Fluorescent Proteins)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171108
[Lr] Data última revisão:
171108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171008
[St] Status:MEDLINE
[do] DOI:10.1186/s12951-017-0300-7


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[PMID]:28950253
[Au] Autor:Shao J; Yin Y; Yin X; Ji L; Xin Y; Zou J; Yao Y
[Ad] Endereço:Department of Ophthalmology, Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi, China.
[Ti] Título:Transthyretin Exerts Pro-Apoptotic Effects in Human Retinal Microvascular Endothelial Cells Through a GRP78-Dependent Pathway in Diabetic Retinopathy.
[So] Source:Cell Physiol Biochem;43(2):788-800, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND/AIMS: Diabetic retinopathy (DR) is one of the main causes of blindness in the world. Our previous study showed that transthyretin (TTR) regulates key genes in the Tie2 pathway and inhibits the development of neovascularization in DR, but the mechanism is still unclear. Here, we investigated how TTR affects the progression of neovascularization in DR. METHODS: Natural and simulated DR media (hyperglycemia and hypoxia) were used to culture human retinal microvascular endothelial cells (hRECs). Flow cytometry was employed to investigate the effect of TTR on apoptosis of hRECs. Fluorescent labeling and immunofluorescence staining were used to determine the TTR distribution in hRECs. The membrane proteins of hRECs were extracted and applied to a sepharose-TTR column, and the captured proteins were identified by Mass Spectrometric analysis. Gene knock-down and western blotting assays were used to study the key signal pathway of the most abundant identified protein. RESULTS: TTR induced apoptosis of hRECs in an environment that simulated hypoxia. Immunofluorescent staining showed that TTR could enter the nuclei of hRECs. A total of 30 unique TTR-captured proteins were identified by Mass Spectrometry, and glucose-regulated protein 78 (GRP78) was one of the most abundant. Western blotting and gene knock-down indicated that TTR might upregulate GRP78 and facilitate apoptosis through the eIF2α/CHOP pathway. CONCLUSIONS: In the DR environment (hyperglycemia and hypoxia), TTR was shown to repress neovascularization by promoting apoptosis of hRECs through a GRP78-dependent pathway.
[Mh] Termos MeSH primário: Apoptose
Retinopatia Diabética/metabolismo
Retinopatia Diabética/patologia
Proteínas de Choque Térmico/metabolismo
Pré-Albumina/metabolismo
Retina/patologia
Transdução de Sinais
[Mh] Termos MeSH secundário: Células Cultivadas
Células Endoteliais/metabolismo
Células Endoteliais/patologia
Seres Humanos
Retina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Heat-Shock Proteins); 0 (Prealbumin); 0 (molecular chaperone GRP78)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170927
[St] Status:MEDLINE
[do] DOI:10.1159/000481562


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[PMID]:28920684
[Au] Autor:Smith TP; Windsor IW; Forest KT; Raines RT
[Ad] Endereço:Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
[Ti] Título:Stilbene Boronic Acids Form a Covalent Bond with Human Transthyretin and Inhibit Its Aggregation.
[So] Source:J Med Chem;60(18):7820-7834, 2017 Sep 28.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Transthyretin (TTR) is a homotetrameric protein. Its dissociation into monomers leads to the formation of fibrils that underlie human amyloidogenic diseases. The binding of small molecules to the thyroxin-binding sites in TTR stabilizes the homotetramer and attenuates TTR amyloidosis. Herein, we report on boronic acid-substituted stilbenes that limit TTR amyloidosis in vitro. Assays of affinity for TTR and inhibition of its tendency to form fibrils were coupled with X-ray crystallographic analysis of nine TTR·ligand complexes. The ensuing structure-function data led to a symmetrical diboronic acid that forms a boronic ester reversibly with serine 117. This diboronic acid inhibits fibril formation by both wild-type TTR and a common disease-related variant, V30M TTR, as effectively as does tafamidis, a small-molecule drug used to treat TTR-related amyloidosis in the clinic. These findings establish a new modality for covalent inhibition of fibril formation and illuminate a path for future optimization.
[Mh] Termos MeSH primário: Ácidos Borônicos/química
Ácidos Borônicos/farmacologia
Pré-Albumina/metabolismo
Agregados Proteicos/efeitos dos fármacos
Estilbenos/química
Estilbenos/farmacologia
[Mh] Termos MeSH secundário: Amiloidose/tratamento farmacológico
Amiloidose/genética
Amiloidose/metabolismo
Cristalografia por Raios X
Seres Humanos
Ligantes
Modelos Moleculares
Mutação Puntual
Pré-Albumina/química
Pré-Albumina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Boronic Acids); 0 (Ligands); 0 (Prealbumin); 0 (Protein Aggregates); 0 (Stilbenes)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170919
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00952


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[PMID]:28920433
[Au] Autor:Sun X; Dyson HJ; Wright PE
[Ad] Endereço:Department of Integrative Structural and Computational Biology and Skaggs Institute of Chemical Biology, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
[Ti] Título:Fluorotryptophan Incorporation Modulates the Structure and Stability of Transthyretin in a Site-Specific Manner.
[So] Source:Biochemistry;56(41):5570-5581, 2017 Oct 17.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Abnormal deposition of aggregated wild-type (WT) human transthyretin (TTR) and its pathogenic variants is responsible for cardiomyopathy and neuropathy related to TTR amyloidosis. The tryptophan (Trp) fluorescence measurements typically used to study structural changes of TTR do not yield site-specific information on the two Trp residues per TTR protomer. To obtain such information, tryptophan labeled with fluorine at the 5 and 6 positions (5FW and 6FW) was incorporated into TTR. Fluorescence of 5FW and 6FW-labeled WT-TTR (WT-5FW and WT-6FW) and a single-Trp mutant W41Y showed that the photophysics of incorporated fluoro-Trp is consistent with site-specific solvation of the indole ring of W41 and W79. F-NMR showed that solvent accessibility depends on both the location of the Trp and the position of the fluorine substituent in the indole ring. Unexpectedly, differences were observed in the rates of aggregation, with WT-6FW aggregating more rapidly than WT-5FW or WT-TTR. Real-time F-NMR urea unfolding experiments revealed that WT-5FW is kinetically more stable than WT-6FW, consistent with the aggregation assay. In addition, structural perturbations of residues distant from either Trp site are more extensive in WT-6FW. Notably, residues in the dimer interfaces are perturbed by 6FW at residue 79; pathogenic mutations in these regions are associated with reduced tetramer stability and amyloidogenesis. The differences in behavior that arise from the replacement of a fluorine at the 5-position of a tryptophan with one at the adjacent 6-position emphasize the delicate balance of stability in the TTR tetramer.
[Mh] Termos MeSH primário: Modelos Moleculares
Pré-Albumina/química
Triptofano/química
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Dimerização
Corantes Fluorescentes/química
Cinética
Mutação
Ressonância Magnética Nuclear Biomolecular
Pré-Albumina/genética
Pré-Albumina/metabolismo
Agregação Patológica de Proteínas/genética
Agregação Patológica de Proteínas/metabolismo
Conformação Proteica
Desnaturação Proteica/efeitos dos fármacos
Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos
Multimerização Proteica/efeitos dos fármacos
Estabilidade Proteica/efeitos dos fármacos
Desdobramento de Proteína/efeitos dos fármacos
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Triptofano/análogos & derivados
Ureia/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fluorescent Dyes); 0 (Prealbumin); 0 (Recombinant Proteins); 343-91-9 (5-fluorotryptophan); 343-92-0 (6-fluorotryptophan); 8DUH1N11BX (Tryptophan); 8W8T17847W (Urea)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171121
[Lr] Data última revisão:
171121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170919
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00815


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[PMID]:28898054
[Au] Autor:Müller C; Farkas R; Borgna F; Schmid RM; Benesová M; Schibli R
[Ad] Endereço:Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut , 5232 Villigen-PSI, Switzerland.
[Ti] Título:Synthesis, Radiolabeling, and Characterization of Plasma Protein-Binding Ligands: Potential Tools for Modulation of the Pharmacokinetic Properties of (Radio)Pharmaceuticals.
[So] Source:Bioconjug Chem;28(9):2372-2383, 2017 Sep 20.
[Is] ISSN:1520-4812
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The development of (radio)pharmaceuticals with favorable pharmacokinetic profiles is crucial for allowing the optimization of the imaging or therapeutic potential and the minimization of undesired side effects. The aim of this study was, therefore, to evaluate and compare three different plasma protein binders (PPB-01, PPB-02, and PPB-03) that are potentially useful in combination with (radio)pharmaceuticals to enhance their half-life in the blood. The entities were functionalized with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator via a l-lysine and ß-alanine linker moiety using solid-phase peptide chemistry and labeled with Lu (T = 6.65 days), a clinically established radiometal. The binding capacities of these radioligands and Lu-DOTA were evaluated using human plasma and solutions of human serum albumin (HSA), human α -acid glycoprotein (α -AGP), and human transthyretin (hTTR) by applying an ultrafiltration assay. Lu-DOTA-PPB-01 and Lu-DOTA-PPB-02 bound to a high and moderate extent to human plasma proteins (>90% and ∼70%, respectively), whereas the binding to hTTR was considered negligible (<10%). Lu-DOTA-PPB-03 showed almost complete binding to human plasma proteins (>90%) with a high fraction bound to hTTR (∼50%). Plasma protein binding of the Lu-DOTA complex, which was used as a control, was not observed (<1%). Lu-DOTA-PPB-01 and Lu-DOTA-PPB-02 were both displaced (>80%) from HSA by ibuprofen, specific for Sudlow's binding site II and coherent with the aromatic structures, and >80% by their respective binding entities. Lu-DOTA-PPB-03 was displaced from hTTR by the site-marker l-thyroxine (>60%) and by its binding entity PPB-03* (>80%). All three radioligands were investigated with regard to the in vivo blood clearance in normal mice. Lu-DOTA-PPB-01 showed the slowest blood clearance (T : >15 h) followed by Lu-DOTA-PPB-03 (T : ∼2.33 h) and Lu-DOTA-PPB-02 (T : ∼1.14 h), which was excreted relatively fast. Our results confirmed the high affinity of the 4-(4-iodophenyl)-butyric acid entity (PPB-01) to plasma proteins, while replacement of the halogen by an ethynyl entity (PPB-02) reduced the plasma protein binding significantly. An attractive approach is the application of the transthyretin binder (PPB-03), which shows high affinity to hTTR. Future studies in our laboratory will be focused on the application of these binding entities in combination with clinically relevant targeting agents for diagnostic and therapeutic purposes in nuclear medicine.
[Mh] Termos MeSH primário: Proteínas Sanguíneas/metabolismo
Lutécio/metabolismo
Compostos Radiofarmacêuticos/metabolismo
[Mh] Termos MeSH secundário: Animais
Feminino
Seres Humanos
Ligantes
Lutécio/química
Lutécio/farmacocinética
Camundongos Endogâmicos BALB C
Pré-Albumina/metabolismo
Ligação Proteica
Radioisótopos/química
Radioisótopos/metabolismo
Radioisótopos/farmacocinética
Compostos Radiofarmacêuticos/química
Compostos Radiofarmacêuticos/farmacocinética
Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único/métodos
Tiroxina/metabolismo
Distribuição Tecidual
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Blood Proteins); 0 (Ligands); 0 (Prealbumin); 0 (Radioisotopes); 0 (Radiopharmaceuticals); 5H0DOZ21UJ (Lutetium); Q51BO43MG4 (Thyroxine)
[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:170913
[St] Status:MEDLINE
[do] DOI:10.1021/acs.bioconjchem.7b00378


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[PMID]:28820582
[Au] Autor:Lim KH; Dasari AKR; Ma R; Hung I; Gan Z; Kelly JW; Fitzgerald MC
[Ad] Endereço:Department of Chemistry, East Carolina University , Greenville, North Carolina 27858, United States.
[Ti] Título:Pathogenic Mutations Induce Partial Structural Changes in the Native ß-Sheet Structure of Transthyretin and Accelerate Aggregation.
[So] Source:Biochemistry;56(36):4808-4818, 2017 Sep 12.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Amyloid formation of natively folded proteins involves global and/or local unfolding of the native state to form aggregation-prone intermediates. Here we report solid-state nuclear magnetic resonance (NMR) structural studies of amyloid derived from wild-type (WT) and more aggressive mutant forms of transthyretin (TTR) to investigate the structural changes associated with effective TTR aggregation. We employed selective C labeling schemes to investigate structural features of ß-structured core regions in amyloid states of WT and two mutant forms (V30M and L55P) of TTR. Analyses of the C- C correlation solid-state NMR spectra revealed that WT TTR aggregates contain an amyloid core consisting of nativelike CBEF and DAGH ß-sheet structures, and the mutant TTR amyloids adopt a similar amyloid core structure with nativelike CBEF and AGH ß-structures. However, the V30M mutant amyloid was shown to have a different DA ß-structure. In addition, strand D is more disordered even in the native state of L55P TTR, indicating that the pathogenic mutations affect the DA ß-structure, leading to more effective amyloid formation. The NMR results are consistent with our mass spectrometry-based thermodynamic analyses that showed the amyloidogenic precursor states of WT and mutant TTRs adopt folded structures but the mutant precursor states are less stable than that of WT TTR. Analyses of the oxidation rate of the methionine side chain also revealed that the side chain of residue Met-30 pointing between strands D and A is not protected from oxidation in the V30M mutant, while protected in the native state, supporting the possibility that the DA ß-structure might be disrupted in the V30M mutant amyloid.
[Mh] Termos MeSH primário: Pré-Albumina/química
[Mh] Termos MeSH secundário: Dicroísmo Circular
Escherichia coli/metabolismo
Expressão Gênica
Espectroscopia de Ressonância Magnética
Modelos Moleculares
Mutação
Oxirredução
Ligação Proteica
Conformação Proteica
Dobramento de Proteína
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Prealbumin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170819
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00658


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[PMID]:28711731
[Au] Autor:Deng L; Xue X; Shen C; Song X; Wang C; Wang N
[Ad] Endereço:Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
[Ti] Título:Insulin chains as efficient fusion tags for prokaryotic expression of short peptides.
[So] Source:Protein Expr Purif;138:46-55, 2017 Oct.
[Is] ISSN:1096-0279
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Insulin chains are usually expressed in Escherichia coli as fusion proteins with different tags, including various low molecular weight peptide tags. The objective of this study was to determine if insulin chains could facilitate the recombinant expression of other target proteins, with an emphasis on low molecular weight peptides. A series of short peptides were fused to mini-proinsulin, chain B or chain A, and induced for expression in Escherichia coli. All the tested peptides including glucagon-like peptide 1 (GLP-1), a C-terminal extended GLP-1, oxyntomodulin, enfuvirtide, linaclotide, and an unstructured artificial peptide were expressed with reasonable yields, identified by Tricine-SDS-PAGE and immunoblotting. All recombinant products were expressed in inclusion bodies. The effective accumulation of products was largely attributed to the insoluble expression induced by fusion with insulin chains, and was confirmed by the fusion expression of transthyretin. Insulin chains thus show promise as efficient fusion tags for mass production of heterologous peptides in prokaryotes.
[Mh] Termos MeSH primário: Vetores Genéticos/metabolismo
Peptídeo 1 Semelhante ao Glucagon/genética
Proteína gp41 do Envelope de HIV/genética
Fragmentos de Peptídeos/genética
Peptídeos/genética
Proinsulina/genética
Proteínas Recombinantes de Fusão/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Western Blotting
Clonagem Molecular
Eletroforese em Gel de Poliacrilamida
Escherichia coli/genética
Escherichia coli/metabolismo
Expressão Gênica
Vetores Genéticos/química
Peptídeo 1 Semelhante ao Glucagon/isolamento & purificação
Peptídeo 1 Semelhante ao Glucagon/metabolismo
Proteína gp41 do Envelope de HIV/isolamento & purificação
Proteína gp41 do Envelope de HIV/metabolismo
Seres Humanos
Corpos de Inclusão/química
Peso Molecular
Fragmentos de Peptídeos/isolamento & purificação
Fragmentos de Peptídeos/metabolismo
Peptídeos/isolamento & purificação
Peptídeos/metabolismo
Pré-Albumina/genética
Pré-Albumina/isolamento & purificação
Pré-Albumina/metabolismo
Proinsulina/isolamento & purificação
Proinsulina/metabolismo
Proteínas Recombinantes de Fusão/isolamento & purificação
Proteínas Recombinantes de Fusão/metabolismo
Temperatura Ambiente
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HIV Envelope Protein gp41); 0 (Peptide Fragments); 0 (Peptides); 0 (Prealbumin); 0 (Recombinant Fusion Proteins); 127279-05-4 (miniproinsulin); 19OWO1T3ZE (enfuvirtide); 89750-14-1 (Glucagon-Like Peptide 1); 9035-68-1 (Proinsulin); N0TXR0XR5X (linaclotide)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170717
[St] Status:MEDLINE


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[PMID]:28704493
[Au] Autor:Saldaño TE; Zanotti G; Parisi G; Fernandez-Alberti S
[Ad] Endereço:Universidad Nacional de Quilmes/CONICET, Bernal, Argentina.
[Ti] Título:Evaluating the effect of mutations and ligand binding on transthyretin homotetramer dynamics.
[So] Source:PLoS One;12(7):e0181019, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Native transthyretin (TTR) homotetramer dissociation is the first step of the fibrils formation process in amyloid disease. A large number of specific point mutations that destabilize TTR quaternary structure have shown pro-amyloidogenic effects. Besides, several compounds have been proposed as drugs in the therapy of TTR amyloidosis due to their TTR tetramer binding affinities, and therefore, contribution to its integrity. In the present paper we have explored key positions sustaining TTR tetramer dynamical stability. We have identified positions whose mutations alter the most the TTR tetramer equilibrium dynamics based on normal mode analysis and their response to local perturbations. We have found that these positions are mostly localized at ß-strands E and F and EF-loop. The monomer-monomer interface is pointed out as one of the most vulnerable regions to mutations that lead to significant changes in the TTR-tetramer equilibrium dynamics and, therefore, induces TTR amyloidosis. Besides, we have found that mutations on residues localized at the dimer-dimer interface and/or at the T4 hormone binding site destabilize the tetramer more than the average. Finally, we were able to compare several compounds according to their effect on vibrations associated to the ligand binding. Our ligand comparison is discussed and analyzed in terms of parameters and measurements associated to TTR-ligand binding affinities and the stabilization of its native state.
[Mh] Termos MeSH primário: Mutação
Pré-Albumina/química
Pré-Albumina/metabolismo
[Mh] Termos MeSH secundário: Algoritmos
Sítios de Ligação
Seres Humanos
Ligantes
Modelos Moleculares
Pré-Albumina/genética
Ligação Proteica
Estabilidade Proteica
Estrutura Quaternária de Proteína
Estrutura Secundária de Proteína
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligands); 0 (Prealbumin)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170714
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181019



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