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1.
Biochemistry ; 62(1): 35-43, 2023 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-36535020

RESUMO

The gene encoding the p53 tumor suppressor protein is the most frequently mutated oncogene in cancer patients; yet, generalized strategies for rescuing the function of different p53 mutants remain elusive. This work investigates factors that may contribute to the low inherent stability of the wild-type p53 core domain (p53C) and structurally compromised Y220C mutant. Pressure-induced unfolding of p53C was compared to p63C, the p53 family member with the highest stability, the engineered superstable p53C hexamutant (p53C HM), and lower stability p53C Y220C cancer-associated mutant. The following pressure unfolding values (P50% bar) were obtained: p53C 3346, p53C Y220C 2217, p53C HM 3943, and p63C 4326. Molecular dynamics (MD) simulations revealed that p53C Y220C was most prone to water infiltration, followed by p53C, whereas the interiors of p53C HM and p63C remained comparably dry. A strong correlation (r2 = 0.92) between P50% and extent of interior hydration was observed. The pathways of individual water molecule entry and exit were mapped and analyzed, revealing a common route preserved across the p53 family involving a previously reported pocket, along with a novel surface cleft, both of which appear to be targetable by small molecules. Potential determinants of propensity to water incursion were assessed, including backbone hydrogen bond protection and combined sequence and structure similarity. Collectively, our results indicate that p53C has an intrinsic susceptibility to water leakage, which is exacerbated in a structural class mutant, suggesting that there may be a common avenue for rescuing p53 function.


Assuntos
Neoplasias , Proteína Supressora de Tumor p53 , Humanos , Proteína Supressora de Tumor p53/metabolismo , Água/metabolismo , Simulação de Dinâmica Molecular , Neoplasias/metabolismo , Fenômenos Biofísicos
2.
Biochim Biophys Acta Gen Subj ; 1865(9): 129949, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34139289

RESUMO

BACKGROUND: The N-terminal domain of Tetracenomycin aromatase/cyclase (TcmN), an enzyme derived from Streptomyces glaucescens, is involved in polyketide cyclization, aromatization, and folding. Polyketides are a diverse class of secondary metabolites produced by certain groups of bacteria, fungi, and plants with various pharmaceutical applications. Examples include antibiotics, such as tetracycline, and anticancer drugs, such as doxorubicin. Because TcmN is a promising enzyme for in vitro production of polyketides, it is important to identify conditions that enhance its thermal resistance and optimize its function. METHODS: TcmN unfolding, stability, and dynamics were evaluated by fluorescence spectroscopy, circular dichroism, nuclear magnetic resonance 15N relaxation experiments, and microsecond molecular dynamics (MD) simulations. RESULTS: TcmN thermal resistance was enhanced at low protein and high salt concentrations, was pH-dependent, and denaturation was irreversible. Conformational dynamics on the µs-ms timescale were detected for residues in the substrate-binding cavity, and two predominant conformers representing opened and closed cavity states were observed in the MD simulations. CONCLUSION: Based on the results, a mechanism was proposed in which the thermodynamics and kinetics of the TcmN conformational equilibrium modulate enzyme function by favoring ligand binding and avoiding aggregation. GENERAL SIGNIFICANCE: Understanding the principles underlying TcmN stability and dynamics may help in designing mutants with optimal properties for biotechnological applications.


Assuntos
Proteínas de Bactérias/metabolismo , Complexos Multienzimáticos/metabolismo , Policetídeos/metabolismo , Streptomyces/enzimologia , Proteínas de Bactérias/química , Sítios de Ligação , Modelos Moleculares , Estrutura Molecular , Complexos Multienzimáticos/química , Policetídeos/química , Agregados Proteicos
3.
Biomolecules ; 10(4)2020 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-32260447

RESUMO

Despite being referred to as the guardian of the genome, when impacted by mutations, p53 can lose its protective functions and become a renegade. The malignant transformation of p53 occurs on multiple levels, such as altered DNA binding properties, acquisition of novel cellular partners, or associating into different oligomeric states. The consequences of these transformations can be catastrophic. Ongoing studies have implicated different oligomeric p53 species as having a central role in cancer biology; however, the correlation between p53 oligomerization status and oncogenic activities in cancer progression remains an open conundrum. In this review, we summarize the roles of different p53 oligomeric states in cancer and discuss potential research directions for overcoming aberrant p53 function associated with them. We address how misfolding and prion-like amyloid aggregation of p53 seem to play a crucial role in cancer development. The misfolded and aggregated states of mutant p53 are prospective targets for the development of novel therapeutic strategies against tumoral diseases.


Assuntos
Neoplasias/metabolismo , Agregados Proteicos , Multimerização Proteica , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/metabolismo , Animais , Humanos , Estrutura Quaternária de Proteína
4.
Pharmacol Rep ; 72(3): 631-640, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32040844

RESUMO

BACKGROUND: The M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2) is one of the key components in the Warburg effect, and an important regulator of cancer cell metabolism. Elevated PKM2 expression is a hallmark of numerous tumor types, making it a promising target for cancer therapy. METHODS: Migration of H1299 lung tumor cells treated with synthetic oleanane triterpenoid derivatives CDDO-Me and CDDO-Im was monitored using scratch and transwell assays. Direct binding and inhibition of PKM2 activity by CDDO-Me was demonstrated by pull-down and activity assays. PKM2 localization in the absence and presence of CDDO-Me or CDDO-Im was determined by subcellular fractionation and immunofluorescence microscopy. Involvement of PKM2 in tumor cell migration was assessed using a stable PKM2 knockdown cell line. RESULTS: We demonstrate that migration of H1299 lung tumor cells is inhibited by CDDO-Me and CDDO-Im in scratch and transwell assays. CDDO-Me binds directly and specifically to recombinant PKM2, leading to a reduction of its catalytic activity. PKM2 knockdown cells exhibit significantly lower migration compared to control cells when subjected to glucose and oxygen deprivation, but not under regular conditions. CONCLUSIONS: The results suggest that PKM2 expression in a tumor-like environment contributes to cell migration, and that PKM2 activity can be down regulated by synthetic triterpenoid derivatives.


Assuntos
Movimento Celular/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Piruvato Quinase/antagonistas & inibidores , Piruvato Quinase/metabolismo , Carcinoma Pulmonar de Células não Pequenas , Linhagem Celular Tumoral , Glucose , Humanos , Hipóxia , Ácido Oleanólico/metabolismo , Ácido Oleanólico/farmacologia
5.
Biochem J ; 477(1): 111-120, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31841126

RESUMO

Aggregation is the cause of numerous protein conformation diseases. A common facet of these maladies is the transition of a protein from its functional native state into higher order forms, such as oligomers and amyloid fibrils. p53 is an essential tumor suppressor that is prone to such conformational transitions, resulting in its compromised ability to avert cancer. This work explores the biophysical properties of early-, mid-, and late-stage p53 core domain (p53C) aggregates. Atomistic and coarse-grained molecular dynamics (MD) simulations suggest that early- and mid-stage p53C aggregates have a polymorphic topology of antiparallel and parallel ß-sheets that localize to the core amyloidogenic sequence. Both topologies involve similar extents of interstrand mainchain hydrogen bonding, while sidechain interactions could play a role in regulating strand orientation. The free energy difference between the antiparallel and parallel states was within statistical uncertainty. Negative stain electron microscopy of mature fibrils shows a wide distribution of fiber widths, indicating that polymorphism may extend to the quaternary structure level. Circular dichroism of the fibrils was indicative of ß-sheet rich structures in atypical conformations. The Raman spectrum of aggregated p53C was consistent with a mixture of arranged ß-sheets and heterogeneous structural elements, which is compatible with the MD findings of an ordered ß-sheet nucleus flanked by disordered structure. Structural polymorphism is a common property of amyloids; however, because certain polymorphs of the same protein can be more harmful than others, going forward it will be pertinent to establish correlations between p53C aggregate structure and pathology.


Assuntos
Agregados Proteicos , Agregação Patológica de Proteínas/metabolismo , Proteína Supressora de Tumor p53/química , Amiloide/metabolismo , Fenômenos Biofísicos , Humanos , Ligação de Hidrogênio , Simulação de Dinâmica Molecular , Conformação Proteica em Folha beta , Domínios Proteicos , Proteína Supressora de Tumor p53/metabolismo
6.
J Biol Chem ; 293(29): 11374-11387, 2018 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-29853637

RESUMO

The functionality of the tumor suppressor p53 is altered in more than 50% of human cancers, and many individuals with cancer exhibit amyloid-like buildups of aggregated p53. An understanding of what triggers the pathogenic amyloid conversion of p53 is required for the further development of cancer therapies. Here, perturbation of the p53 core domain (p53C) with subdenaturing concentrations of guanidine hydrochloride and high hydrostatic pressure revealed native-like molten globule (MG) states, a subset of which were highly prone to amyloidogenic aggregation. We found that MG conformers of p53C, probably representing population-weighted averages of multiple states, have different volumetric properties, as determined by pressure perturbation and size-exclusion chromatography. We also found that they bind the fluorescent dye 4,4'-dianilino-1,1'-binaphthyl-5,5'-disulfonic acid (bis-ANS) and have a native-like tertiary structure that occludes the single Trp residue in p53. Fluorescence experiments revealed conformational changes of the single Trp and Tyr residues before p53 unfolding and the presence of MG conformers, some of which were highly prone to aggregation. p53C exhibited marginal unfolding cooperativity, which could be modulated from unfolding to aggregation pathways with chemical or physical forces. We conclude that trapping amyloid precursor states in solution is a promising approach for understanding p53 aggregation in cancer. Our findings support the use of single-Trp fluorescence as a probe for evaluating p53 stability, effects of mutations, and the efficacy of therapeutics designed to stabilize p53.


Assuntos
Neoplasias/metabolismo , Agregação Patológica de Proteínas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Humanos , Modelos Moleculares , Agregados Proteicos , Conformação Proteica , Desnaturação Proteica , Domínios Proteicos , Dobramento de Proteína , Estabilidade Proteica , Termodinâmica , Proteína Supressora de Tumor p53/química
7.
J Phys Chem B ; 122(22): 5851-5859, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29745220

RESUMO

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor and principal regulator of the antioxidant pathway. The Kelch domain of Kelch-like ECH-associated protein 1 (Keap1) binds to motifs in the N-terminal region of Nrf2, promoting its degradation. There is interest in developing ligands that can compete with Nrf2 for binding to Kelch, thereby activating its transcriptional activities and increasing antioxidant levels. Using experimental Δ Gbind values of Kelch-binding motifs determined previously, a revised hydrophobicity-based model was developed for estimating Δ Gbind from amino acid sequence and applied to rank potential uncharacterized Kelch-binding motifs identified from interaction databases and BLAST searches. Model predictions and molecular dynamics (MD) simulations suggested that full-length MAD2A binds Kelch more favorably than a high-affinity 20-mer Nrf2 E78P peptide, but that the motif in isolation is not a particularly strong binder. Endeavoring to develop shorter peptides for activating Nrf2, new designs were created based on the E78P peptide, some of which showed considerable propensity to form binding-competent structures in MD, and were predicted to interact with Kelch more favorably than the E78P peptide. The peptides could be promising new ligands for enhancing the oxidative stress response.


Assuntos
Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Sequência de Aminoácidos , Antioxidantes/química , Antioxidantes/metabolismo , Sítios de Ligação , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/química , Simulação de Dinâmica Molecular , Fator 2 Relacionado a NF-E2/química , Peptídeos/química , Peptídeos/metabolismo , Ligação Proteica , Termodinâmica
8.
J Comput Aided Mol Des ; 32(5): 591-605, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29564808

RESUMO

Chagas disease remains a major health problem in South America, and throughout the world. The two drugs clinically available for its treatment have limited efficacy and cause serious adverse effects. Cruzain is an established therapeutic target of Trypanosoma cruzi, the protozoan that causes Chagas disease. Our group recently identified a competitive cruzain inhibitor (compound 1) with an IC50 = 15 µM that is also more synthetically accessible than the previously reported lead, compound 2. Prior studies, however, did not propose a binding mode for compound 1, hindering understanding of the structure-activity relationship and optimization. Here, the cruzain binding mode of compound 1 was investigated using docking, molecular dynamics (MD) simulations with ab initio derived parameters, ab initio calculations, and MM/PBSA. Two ligand protonation states and four binding poses were evaluated. A careful ligand parameterization method was employed to derive more physically meaningful parameters than those obtained by automated tools. The poses of unprotonated 1 were unstable in MD, showing large conformational changes and diffusing away from the binding site, whereas the protonated form showed higher stability and interaction with negatively charged residues Asp161 and Cys25. MM/PBSA also suggested that these two residues contribute favorably to binding of compound 1. By combining results from MD, ab initio calculations, and MM/PBSA, a binding mode of 1 is proposed. The results also provide insights for further optimization of 1, an interesting lead compound for the development of new cruzain inhibitors.


Assuntos
Inibidores de Cisteína Proteinase/química , Modelos Moleculares , Proteínas de Protozoários/antagonistas & inibidores , Quinolinas/química , Cisteína Endopeptidases , Desenho de Fármacos , Ligantes , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade , Termodinâmica
9.
Acc Chem Res ; 51(1): 181-190, 2018 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-29260852

RESUMO

Prion-like behavior of several amyloidogenic proteins has been demonstrated in recent years. Despite having functional roles in some cases, irregular aggregation can have devastating consequences. The most commonly known amyloid diseases are Alzheimer's, Parkinson's, and Transmissible Spongiform Encephalopathies (TSEs). The pathophysiology of prion-like diseases involves the structural transformation of wild-type (wt) proteins to transmissible forms that can convert healthy proteins, generating aggregates. The mutant form of tumor suppressor protein, p53, has recently been shown to exhibit prion-like properties. Within the context of p53 aggregation and the search for ways to avert it, this review emphasizes discoveries, approaches, and research from our laboratory and others. Although its standard functions are strongly connected to tumor suppression, p53 mutants and aggregates are involved in cancer progression. p53 aggregates are heterogeneous assemblies composed of amorphous aggregates, oligomers, and amyloid-like fibrils. Evidence of these structures in tumor tissues, the in vitro capability for p53 mutants to coaggregate with wt protein, and the detection of cell-to-cell transmission indicate that cancer has the basic characteristics of prion and prion-like diseases. Various approaches aim to restore p53 functions in cancer. Methods include the use of small-molecule and peptide stabilizers of mutant p53, zinc administration, gene therapy, alkylating and DNA intercalators, and blockage of p53-MDM2 interaction. A primary challenge in developing small-molecule inhibitors of p53 aggregation is the large number of p53 mutations. Another issue is the inability to recover p53 function by dissociating mature fibrils. Consequently, efforts have emerged to target the intermediate species of the aggregation reaction. Φ-value analysis has been used to characterize the kinetics of the early phases of p53 aggregation. Our experiments using high hydrostatic pressure (HHP) and chemical denaturants have helped to clarify excited conformers of p53 that are prone to aggregation. Molecular dynamics (MD) and phasor analysis of single Trp fluorescence signals point toward the presence of preamyloidogenic conformations of p53, which are not observed for p63 or p73. Exploring the features of competent preamyloidogenic states of wt and different p53 mutants may provide a framework for designing personalized drugs for the restoration of p53 function. Protection of backbone hydrogen bonds (BHBs) has been shown to be an important factor for the stability of amyloidogenic proteins and was employed to identify and stabilize the structural defect resulting from the p53 Y220C mutation. Using MD simulations, we compared BHB protection factors between p53 family members to determine the donor-acceptor pairs in p53 that exhibit lower protection. The identification of structurally vulnerable sites in p53 should provide new insights into rational designs that can rapidly be screened using our experimental methodology. Through continued and combined efforts, the outlook is positive for the development of strategies for regulating p53 amyloid transformation.


Assuntos
Neoplasias/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Humanos , Ligação de Hidrogênio , Simulação de Dinâmica Molecular , Estrutura Molecular , Mutação , Neoplasias/química , Agregados Proteicos , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/genética
10.
Sci Rep ; 6: 32535, 2016 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-27600721

RESUMO

The p53 family of proteins is comprised of p53, p63 and p73. Because the p53 DNA binding domain (DBD) is naturally unstable and possesses an amyloidogenic sequence, it is prone to form amyloid fibrils, causing loss of functions. To develop p53 therapies, it is necessary to understand the molecular basis of p53 instability and aggregation. Light scattering, thioflavin T (ThT) and high hydrostatic pressure (HHP) assays showed that p53 DBD aggregates faster and to a greater extent than p63 and p73 DBDs, and was more susceptible to denaturation. The aggregation tendencies of p53, p63, and p73 DBDs were strongly correlated with their thermal stabilities. Molecular Dynamics (MD) simulations indicated specific regions of structural heterogeneity unique to p53, which may be promoted by elevated incidence of exposed backbone hydrogen bonds (BHBs). The results indicate regions of structural vulnerability in the p53 DBD, suggesting new targetable sites for modulating p53 stability and aggregation, a potential approach to cancer therapy.


Assuntos
Família Multigênica , Agregados Proteicos , Proteína Supressora de Tumor p53/metabolismo , Sequência de Aminoácidos , Humanos , Ligação de Hidrogênio , Pressão , Desnaturação Proteica , Domínios Proteicos , Estabilidade Proteica , Proteína Supressora de Tumor p53/química
11.
Artigo em Inglês | MEDLINE | ID: mdl-27549118

RESUMO

Prion diseases are disorders that share several characteristics that are typical of many neurodegenerative diseases. Recently, several studies have extended the prion concept to pathological aggregation in malignant tumors involving misfolded p53, a tumor-suppressor protein. The aggregation of p53 and its coaggregation with p53 family members, p63 and p73, have been shown. Certain p53 mutants exert a dominant-negative regulatory effect on wild-type (WT) p53. The basis for this dominant-negative effect is that amyloid-like mutant p53 converts WT p53 into an aggregated species, leading to a gain-of-function (GoF) phenotype and the loss of its tumor-suppressor function. Recently, it was shown that p53 aggregates can be internalized by cells and can coaggregate with endogenous p53, corroborating the prion-like properties of p53 aggregates. The prion-like behavior of oncogenic p53 mutants provides an explanation for its dominant-negative and GoF properties, including the high metastatic potential of cancer cells carrying p53 mutations. The inhibition of p53 aggregation appears to represent a promising target for therapeutic intervention in patients with malignant tumors.


Assuntos
Neoplasias/metabolismo , Doenças Priônicas/metabolismo , Príons/metabolismo , Dobramento de Proteína , Proteínas Supressoras de Tumor/metabolismo , Genes p53 , Humanos , Proteínas Intrinsicamente Desordenadas/metabolismo , Neoplasias/genética , Ligação Proteica
12.
Biomol NMR Assign ; 10(1): 49-51, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26294377

RESUMO

p53, p63, p73 family of proteins are transcription factors with crucial roles in regulating cellular processes such apoptosis, proliferation, differentiation, and DNA damage response. The three family members have both overlapping and unique biological functions. Sequence and structural homology are greatest in the DNA binding domains (DBD), which is the site of the majority of p53 mutations. Structurally unstable p53 DBD mutants can associate with themselves or p63 and p73 DBDs, impeding tumor suppressor functions. Evidence suggests that these proteins associate to form amyloid-like oligomers and fibrils through an aggregation-prone sequence within the DBDs. Despite having high sequence and structure similarities, p63 and p73 DBDs appear to have considerably lower tendencies to be incorporated into p53 aggregates, relative to p53. The backbone resonance assignments of p73 DBD reported here complement those previously reported for p53 and p63, allowing comparisons and providing molecular insights into their biological functions and roles in aggregation and tumor development.


Assuntos
DNA/metabolismo , Ressonância Magnética Nuclear Biomolecular , Proteína Tumoral p73/química , Proteína Tumoral p73/metabolismo , Humanos , Ligação Proteica , Domínios Proteicos
13.
Sci Rep ; 3: 2305, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23892546

RESUMO

A small number of proteins, called hubs, have high connectivity and are essential for interactome functionality and integrity. Keap1 is a crucial hub in the oxidative stress response and apoptosis. The Kelch domain of Keap1 preferentially binds to disordered regions of its partners, which share similar binding motifs, but have a wide range of binding affinities. Isothermal titration calorimetry (ITC) and multi-microsecond molecular dynamics (MD) simulations were used to determine the factors that govern the affinity of all currently known disordered binding partners to Kelch. Our results show that the affinities to this hub are largely determined by the extent of preformed bound state-like conformation in the free state structures of these disordered targets. Based on our findings, we have designed a high-affinity peptide that can specifically disrupt the Keap1-NRF2 interaction and has the potential for therapeutic applications.


Assuntos
Proteínas Intrinsicamente Desordenadas/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Sítios de Ligação , Proteínas Intrinsicamente Desordenadas/química , Modelos Moleculares , Dados de Sequência Molecular , Peptídeos/química , Peptídeos/metabolismo , Matrizes de Pontuação de Posição Específica , Conformação Proteica , Dobramento de Proteína , Domínios e Motivos de Interação entre Proteínas , Alinhamento de Sequência , Termodinâmica
14.
PLoS One ; 6(11): e27371, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22125611

RESUMO

Intrinsically disordered proteins (IDPs) are abundant in cells and have central roles in protein-protein interaction networks. Interactions between the IDP Prothymosin alpha (ProTα) and the Neh2 domain of Nuclear factor erythroid 2-related factor 2 (Nrf2), with a common binding partner, Kelch-like ECH-associated protein 1(Keap1), are essential for regulating cellular response to oxidative stress. Misregulation of this pathway can lead to neurodegenerative diseases, premature aging and cancer. In order to understand the mechanisms these two disordered proteins employ to bind to Keap1, we performed extensive 0.5-1.0 microsecond atomistic molecular dynamics (MD) simulations and isothermal titration calorimetry experiments to investigate the structure/dynamics of free-state ProTα and Neh2 and their thermodynamics of bindings. The results show that in their free states, both ProTα and Neh2 have propensities to form bound-state-like ß-turn structures but to different extents. We also found that, for both proteins, residues outside the Keap1-binding motifs may play important roles in stabilizing the bound-state-like structures. Based on our findings, we propose that the binding of disordered ProTα and Neh2 to Keap1 occurs synergistically via preformed structural elements (PSEs) and coupled folding and binding, with a heavy bias towards PSEs, particularly for Neh2. Our results provide insights into the molecular mechanisms Neh2 and ProTα bind to Keap1, information that is useful for developing therapeutics to enhance the oxidative stress response.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/química , Simulação de Dinâmica Molecular , Fator 2 Relacionado a NF-E2/química , Precursores de Proteínas/química , Timosina/análogos & derivados , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Sítios de Ligação , Calorimetria/métodos , Cristalografia por Raios X , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch , Modelos Moleculares , Dados de Sequência Molecular , Fator 2 Relacionado a NF-E2/metabolismo , Ligação Proteica , Precursores de Proteínas/metabolismo , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Homologia de Sequência de Aminoácidos , Termodinâmica , Timosina/química , Timosina/metabolismo , Fatores de Tempo
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