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1.
Cell ; 187(11): 2735-2745.e12, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38723628

RESUMO

Hepatitis B virus (HBV) is a small double-stranded DNA virus that chronically infects 296 million people. Over half of its compact genome encodes proteins in two overlapping reading frames, and during evolution, multiple selective pressures can act on shared nucleotides. This study combines an RNA-based HBV cell culture system with deep mutational scanning (DMS) to uncouple cis- and trans-acting sequence requirements in the HBV genome. The results support a leaky ribosome scanning model for polymerase translation, provide a fitness map of the HBV polymerase at single-nucleotide resolution, and identify conserved prolines adjacent to the HBV polymerase termination codon that stall ribosomes. Further experiments indicated that stalled ribosomes tether the nascent polymerase to its template RNA, ensuring cis-preferential RNA packaging and reverse transcription of the HBV genome.


Assuntos
Vírus da Hepatite B , Transcrição Reversa , Humanos , Genoma Viral/genética , Vírus da Hepatite B/genética , Mutação , Ribossomos/metabolismo , RNA Viral/genética , RNA Viral/metabolismo , Linhagem Celular
2.
Genes Dev ; 36(9-10): 634-646, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35654455

RESUMO

In response to starvation, endospore-forming bacteria differentiate into stress-resistant spores that can remain dormant for years yet rapidly germinate and resume growth in response to nutrients. The small molecule dipicolinic acid (DPA) plays a central role in both the stress resistance of the dormant spore and its exit from dormancy during germination. The spoVA locus is required for DPA import during sporulation and has been implicated in its export during germination, but the molecular bases are unclear. Here, we define the minimal set of proteins encoded in the Bacillus subtilis spoVA operon required for DPA import and demonstrate that these proteins form a membrane complex. Structural modeling of these components combined with mutagenesis and in vivo analysis reveal that the C and Eb subunits form a membrane channel, while the D subunit functions as a cytoplasmic plug. We show that point mutations that impair the interactions between D and the C-Eb membrane complex reduce the efficiency of DPA import during sporulation and reciprocally accelerate DPA release during germination. Our data support a model in which DPA transport into spores involves cycles of unplugging and then replugging the C-Eb membrane channel, while nutrient detection during germination triggers DPA release by unplugging it.


Assuntos
Proteínas de Bactérias , Esporos Bacterianos , Bacillus subtilis/genética , Bacillus subtilis/metabolismo , Proteínas de Bactérias/metabolismo , Ácidos Picolínicos/metabolismo , Esporos Bacterianos/genética
3.
Nat Chem Biol ; 19(8): 1013-1021, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37081311

RESUMO

The relaxin family peptide receptor 1 (RXFP1) is the receptor for relaxin-2, an important regulator of reproductive and cardiovascular physiology. RXFP1 is a multi-domain G protein-coupled receptor (GPCR) with an ectodomain consisting of a low-density lipoprotein receptor class A (LDLa) module and leucine-rich repeats. The mechanism of RXFP1 signal transduction is clearly distinct from that of other GPCRs, but remains very poorly understood. In the present study, we determine the cryo-electron microscopy structure of active-state human RXFP1, bound to a single-chain version of the endogenous agonist relaxin-2 and the heterotrimeric Gs protein. Evolutionary coupling analysis and structure-guided functional experiments reveal that RXFP1 signals through a mechanism of autoinhibition. Our results explain how an unusual GPCR family functions, providing a path to rational drug development targeting the relaxin receptors.


Assuntos
Relaxina , Humanos , Relaxina/química , Relaxina/metabolismo , Microscopia Crioeletrônica , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Peptídeos/química
4.
Proc Natl Acad Sci U S A ; 115(26): 6709-6714, 2018 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-29891673

RESUMO

The peptidoglycan cell wall provides an essential protective barrier in almost all bacteria, defining cellular morphology and conferring resistance to osmotic stress and other environmental hazards. The precursor to peptidoglycan, lipid II, is assembled on the inner leaflet of the plasma membrane. However, peptidoglycan polymerization occurs on the outer face of the plasma membrane, and lipid II must be flipped across the membrane by the MurJ protein before its use in peptidoglycan synthesis. Due to its central role in cell wall assembly, MurJ is of fundamental importance in microbial cell biology and is a prime target for novel antibiotic development. However, relatively little is known regarding the mechanisms of MurJ function, and structural data for MurJ are available only from the extremophile Thermosipho africanus Here, we report the crystal structure of substrate-free MurJ from the gram-negative model organism Escherichia coli, revealing an inward-open conformation. Taking advantage of the genetic tractability of E. coli, we performed high-throughput mutagenesis and next-generation sequencing to assess mutational tolerance at every amino acid in the protein, providing a detailed functional and structural map for the enzyme and identifying sites for inhibitor development. Lastly, through the use of sequence coevolution analysis, we identify functionally important interactions in the outward-open state of the protein, supporting a rocker-switch model for lipid II transport.


Assuntos
Proteínas de Escherichia coli/química , Proteínas de Transferência de Fosfolipídeos/química , Cristalografia por Raios X , Proteínas de Escherichia coli/genética , Evolução Molecular , Biblioteca Gênica , Bacilos Gram-Negativos Anaeróbios Retos, Helicoidais e Curvos/enzimologia , Sequenciamento de Nucleotídeos em Larga Escala , Modelos Moleculares , Mutação , Proteínas de Transferência de Fosfolipídeos/genética , Conformação Proteica , Proteínas Recombinantes de Fusão/química , Relação Estrutura-Atividade
5.
Proteins ; 87(12): 1315-1332, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31603581

RESUMO

CASP13 has investigated the impact of sparse NMR data on the accuracy of protein structure prediction. NOESY and 15 N-1 H residual dipolar coupling data, typical of that obtained for 15 N,13 C-enriched, perdeuterated proteins up to about 40 kDa, were simulated for 11 CASP13 targets ranging in size from 80 to 326 residues. For several targets, two prediction groups generated models that are more accurate than those produced using baseline methods. Real NMR data collected for a de novo designed protein were also provided to predictors, including one data set in which only backbone resonance assignments were available. Some NMR-assisted prediction groups also did very well with these data. CASP13 also assessed whether incorporation of sparse NMR data improves the accuracy of protein structure prediction relative to nonassisted regular methods. In most cases, incorporation of sparse, noisy NMR data results in models with higher accuracy. The best NMR-assisted models were also compared with the best regular predictions of any CASP13 group for the same target. For six of 13 targets, the most accurate model provided by any NMR-assisted prediction group was more accurate than the most accurate model provided by any regular prediction group; however, for the remaining seven targets, one or more regular prediction method provided a more accurate model than even the best NMR-assisted model. These results suggest a novel approach for protein structure determination, in which advanced prediction methods are first used to generate structural models, and sparse NMR data is then used to validate and/or refine these models.


Assuntos
Espectroscopia de Ressonância Magnética/métodos , Modelos Moleculares , Conformação Proteica , Dobramento de Proteína , Proteínas/química , Algoritmos , Simulação por Computador , Cristalografia por Raios X , Reprodutibilidade dos Testes
6.
Adv Exp Med Biol ; 1105: 153-169, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30617828

RESUMO

While 3D structure determination of small (<15 kDa) proteins by solution NMR is largely automated and routine, structural analysis of larger proteins is more challenging. An emerging hybrid strategy for modeling protein structures combines sparse NMR data that can be obtained for larger proteins with sequence co-variation data, called evolutionary couplings (ECs), obtained from multiple sequence alignments of protein families. This hybrid "EC-NMR" method can be used to accurately model larger (15-60 kDa) proteins, and more rapidly determine structures of smaller (5-15 kDa) proteins using only backbone NMR data. The resulting structures have accuracies relative to reference structures comparable to those obtained with full backbone and sidechain NMR resonance assignments. The requirement that evolutionary couplings (ECs) are consistent with NMR data recorded on a specific member of a protein family, under specific conditions, potentially also allows identification of ECs that reflect alternative allosteric or excited states of the protein structure.


Assuntos
Evolução Molecular , Ressonância Magnética Nuclear Biomolecular , Conformação Proteica , Proteínas/química , Alinhamento de Sequência
7.
Science ; 380(6643): 387-391, 2023 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-37104613

RESUMO

Bacterial spores resist antibiotics and sterilization and can remain metabolically inactive for decades, but they can rapidly germinate and resume growth in response to nutrients. Broadly conserved receptors embedded in the spore membrane detect nutrients, but how spores transduce these signals remains unclear. Here, we found that these receptors form oligomeric membrane channels. Mutations predicted to widen the channel initiated germination in the absence of nutrients, whereas those that narrow it prevented ion release and germination in response to nutrients. Expressing receptors with widened channels during vegetative growth caused loss of membrane potential and cell death, whereas the addition of germinants to cells expressing wild-type receptors triggered membrane depolarization. Therefore, germinant receptors act as nutrient-gated ion channels such that ion release initiates exit from dormancy.


Assuntos
Bacillus megaterium , Bacillus subtilis , Proteínas de Bactérias , Canais Iônicos , Esporos Bacterianos , Proteínas de Bactérias/genética , Canais Iônicos/genética , Canais Iônicos/metabolismo , Mutação , Esporos Bacterianos/genética , Esporos Bacterianos/metabolismo , Bacillus subtilis/genética , Bacillus subtilis/metabolismo , Bacillus megaterium/genética , Bacillus megaterium/metabolismo
8.
Sci Adv ; 8(28): eabo1126, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35857511

RESUMO

The transmembrane (TM) channel-like 1 (TMC1) and TMC2 proteins play a central role in auditory transduction, forming ion channels that convert sound into electrical signals. However, the molecular mechanism of their gating remains unknown. Here, using predicted structural models as a guide, we probed the effects of 12 mutations on the mechanical gating of the transduction currents in native hair cells of Tmc1/2-null mice expressing virally introduced TMC1 variants. Whole-cell electrophysiological recordings revealed that mutations within the pore-lining TM4 and TM6 helices modified gating, reducing the force sensitivity or shifting the open probability of the channels, or both. For some of the mutants, these changes were accompanied by a change in single-channel conductance. Our observations are in line with a model wherein conformational changes in the TM4 and TM6 helices are involved in the mechanical gating of the transduction channel.

9.
ACS Synth Biol ; 11(3): 1292-1302, 2022 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-35176859

RESUMO

Many organisms can survive extreme conditions and successfully recover to normal life. This extremotolerant behavior has been attributed in part to repetitive, amphipathic, and intrinsically disordered proteins that are upregulated in the protected state. Here, we assemble a library of approximately 300 naturally occurring and designed extremotolerance-associated proteins to assess their ability to protect human cells from chemically induced apoptosis. We show that several proteins from tardigrades, nematodes, and the Chinese giant salamander are apoptosis-protective. Notably, we identify a region of the human ApoE protein with similarity to extremotolerance-associated proteins that also protects against apoptosis. This region mirrors the phase separation behavior seen with such proteins, like the tardigrade protein CAHS2. Moreover, we identify a synthetic protein, DHR81, that shares this combination of elevated phase separation propensity and apoptosis protection. Finally, we demonstrate that driving protective proteins into the condensate state increases apoptosis protection, and highlights the ability of DHR81 condensates to sequester caspase-7. Taken together, this work draws a link between extremotolerance-associated proteins, condensate formation, and designing human cellular protection.


Assuntos
Proteínas Intrinsicamente Desordenadas , Tardígrados , Animais , Apoptose , Humanos , Proteínas Intrinsicamente Desordenadas/química , Proteínas Intrinsicamente Desordenadas/metabolismo , Tardígrados/metabolismo
10.
Nat Commun ; 12(1): 1396, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33654096

RESUMO

Increasing numbers of protein interactions have been identified in high-throughput experiments, but only a small proportion have solved structures. Recently, sequence coevolution-based approaches have led to a breakthrough in predicting monomer protein structures and protein interaction interfaces. Here, we address the challenges of large-scale interaction prediction at residue resolution with a fast alignment concatenation method and a probabilistic score for the interaction of residues. Importantly, this method (EVcomplex2) is able to assess the likelihood of a protein interaction, as we show here applied to large-scale experimental datasets where the pairwise interactions are unknown. We predict 504 interactions de novo in the E. coli membrane proteome, including 243 that are newly discovered. While EVcomplex2 does not require available structures, coevolving residue pairs can be used to produce structural models of protein interactions, as done here for membrane complexes including the Flagellar Hook-Filament Junction and the Tol/Pal complex.


Assuntos
Aminoácidos/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Evolução Molecular , Genoma Bacteriano , Mapeamento de Interação de Proteínas , Proteínas de Bactérias/química , Sequência de Bases , Escherichia coli/genética , Células Eucarióticas/metabolismo , Proteínas de Membrana/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Proteoma/metabolismo
11.
Nat Commun ; 12(1): 6842, 2021 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-34824238

RESUMO

Bacteria from the orders Bacillales and Clostridiales differentiate into stress-resistant spores that can remain dormant for years, yet rapidly germinate upon nutrient sensing. How spores monitor nutrients is poorly understood but in most cases requires putative membrane receptors. The prototypical receptor from Bacillus subtilis consists of three proteins (GerAA, GerAB, GerAC) required for germination in response to L-alanine. GerAB belongs to the Amino Acid-Polyamine-Organocation superfamily of transporters. Using evolutionary co-variation analysis, we provide evidence that GerAB adopts a structure similar to an L-alanine transporter from this superfamily. We show that mutations in gerAB predicted to disrupt the ligand-binding pocket impair germination, while mutations predicted to function in L-alanine recognition enable spores to respond to L-leucine or L-serine. Finally, substitutions of bulkier residues at these positions cause constitutive germination. These data suggest that GerAB is the L-alanine sensor and that B subunits in this broadly conserved family function in nutrient detection.


Assuntos
Aminoácidos/metabolismo , Proteínas de Bactérias/metabolismo , Proteínas de Membrana/metabolismo , Esporos Bacterianos/fisiologia , Alanina/química , Alanina/metabolismo , Aminoácidos/química , Bacillus subtilis/fisiologia , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Sítios de Ligação , Regulação Bacteriana da Expressão Gênica , Ligantes , Proteínas de Membrana/química , Proteínas de Membrana/genética , Modelos Moleculares , Mutação
12.
Cell Syst ; 10(1): 15-24.e5, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31838147

RESUMO

Natural evolution encodes rich information about the structure and function of biomolecules in the genetic record. Previously, statistical analysis of co-variation patterns in natural protein families has enabled the accurate computation of 3D structures. Here, we explored generating similar information by experimental evolution, starting from a single gene and performing multiple cycles of in vitro mutagenesis and functional selection in Escherichia coli. We evolved two antibiotic resistance proteins, ß-lactamase PSE1 and acetyltransferase AAC6, and obtained hundreds of thousands of diverse functional sequences. Using evolutionary coupling analysis, we inferred residue interaction constraints that were in agreement with contacts in known 3D structures, confirming genetic encoding of structural constraints in the selected sequences. Computational protein folding with interaction constraints then yielded 3D structures with the same fold as natural relatives. This work lays the foundation for a new experimental method (3Dseq) for protein structure determination, combining evolution experiments with inference of residue interactions from sequence information. A record of this paper's Transparent Peer Review process is included in the Supplemental Information.


Assuntos
Evolução Molecular , Proteínas/química , Humanos , Conformação Proteica
13.
Nat Microbiol ; 5(6): 813-820, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32152588

RESUMO

The shape, elongation, division and sporulation (SEDS) proteins are a highly conserved family of transmembrane glycosyltransferases that work in concert with class B penicillin-binding proteins (bPBPs) to build the bacterial peptidoglycan cell wall1-6. How these proteins coordinate polymerization of new glycan strands with their crosslinking to the existing peptidoglycan meshwork is unclear. Here, we report the crystal structure of the prototypical SEDS protein RodA from Thermus thermophilus in complex with its cognate bPBP at 3.3 Å resolution. The structure reveals a 1:1 stoichiometric complex with two extensive interaction interfaces between the proteins: one in the membrane plane and the other at the extracytoplasmic surface. When in complex with a bPBP, RodA shows an approximately 10 Å shift of transmembrane helix 7 that exposes a large membrane-accessible cavity. Negative-stain electron microscopy reveals that the complex can adopt a variety of different conformations. These data define the bPBP pedestal domain as the key allosteric activator of RodA both in vitro and in vivo, explaining how a SEDS-bPBP complex can coordinate its dual enzymatic activities of peptidoglycan polymerization and crosslinking to build the cell wall.


Assuntos
Modelos Moleculares , Complexos Multiproteicos/química , Proteínas de Ligação às Penicilinas/química , Peptidoglicano Glicosiltransferase/química , Multimerização Proteica , Sítios de Ligação , Parede Celular/metabolismo , Estrutura Molecular , Complexos Multiproteicos/metabolismo , Proteínas de Ligação às Penicilinas/metabolismo , Peptidoglicano/metabolismo , Peptidoglicano Glicosiltransferase/metabolismo , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade
14.
Nat Genet ; 51(7): 1170-1176, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209393

RESUMO

We describe an experimental method of three-dimensional (3D) structure determination that exploits the increasing ease of high-throughput mutational scans. Inspired by the success of using natural, evolutionary sequence covariation to compute protein and RNA folds, we explored whether 'laboratory', synthetic sequence variation might also yield 3D structures. We analyzed five large-scale mutational scans and discovered that the pairs of residues with the largest positive epistasis in the experiments are sufficient to determine the 3D fold. We show that the strongest epistatic pairings from genetic screens of three proteins, a ribozyme and a protein interaction reveal 3D contacts within and between macromolecules. Using these experimental epistatic pairs, we compute ab initio folds for a GB1 domain (within 1.8 Å of the crystal structure) and a WW domain (2.1 Å). We propose strategies that reduce the number of mutants needed for contact prediction, suggesting that genomics-based techniques can efficiently predict 3D structure.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas de Bactérias/química , Epistasia Genética , Mutação , Proteínas de Ligação a Poli(A)/química , Conformação Proteica , RNA Catalítico/química , Proteínas de Saccharomyces cerevisiae/química , Fatores de Transcrição/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Bactérias/genética , Humanos , Proteínas de Ligação a Poli(A)/genética , Domínios Proteicos , Dobramento de Proteína , RNA Catalítico/genética , Proteínas de Saccharomyces cerevisiae/genética , Fatores de Transcrição/genética , Proteínas de Sinalização YAP
15.
Methods Enzymol ; 614: 363-392, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30611430

RESUMO

Accurate protein structure determination by solution-state NMR is challenging for proteins greater than about 20kDa, for which extensive perdeuteration is generally required, providing experimental data that are incomplete (sparse) and ambiguous. However, the massive increase in evolutionary sequence information coupled with advances in methods for sequence covariance analysis can provide reliable residue-residue contact information for a protein from sequence data alone. These "evolutionary couplings (ECs)" can be combined with sparse NMR data to determine accurate 3D protein structures. This hybrid "EC-NMR" method has been developed using NMR data for several soluble proteins and validated by comparison with corresponding reference structures determined by X-ray crystallography and/or conventional NMR methods. For small proteins, only backbone resonance assignments are utilized, while for larger proteins both backbone and some sidechain methyl resonance assignments are generally required. ECs can be combined with sparse NMR data obtained on deuterated, selectively protonated protein samples to provide structures that are more accurate and complete than those obtained using such sparse NMR data alone. EC-NMR also has significant potential for analysis of protein structures from solid-state NMR data and for studies of integral membrane proteins. The requirement that ECs are consistent with NMR data recorded on a specific member of a protein family, under specific conditions, also allows identification of ECs that reflect alternative allosteric or excited states of the protein structure.


Assuntos
Algoritmos , Proteínas de Escherichia coli/química , Escherichia coli/química , Evolução Molecular , Ressonância Magnética Nuclear Biomolecular/métodos , Proteínas Periplásmicas de Ligação/química , Software , Análise de Variância , Sítios de Ligação , Cristalografia por Raios X , Bases de Dados de Proteínas , Deutério/química , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Humanos , Marcação por Isótopo , Modelos Moleculares , Proteínas Periplásmicas de Ligação/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Homologia Estrutural de Proteína , Termodinâmica
16.
J Cell Biol ; 217(12): 4080-4091, 2018 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-30327422

RESUMO

Metabolic energy is stored in cells primarily as triacylglycerols in lipid droplets (LDs), and LD dysregulation leads to metabolic diseases. The formation of monolayer-bound LDs from the endoplasmic reticulum (ER) bilayer is poorly understood, but the ER protein seipin is essential to this process. In this study, we report a cryo-electron microscopy structure and functional characterization of Drosophila melanogaster seipin. The structure reveals a ring-shaped dodecamer with the luminal domain of each monomer resolved at ∼4.0 Å. Each luminal domain monomer exhibits two distinctive features: a hydrophobic helix (HH) positioned toward the ER bilayer and a ß-sandwich domain with structural similarity to lipid-binding proteins. This structure and our functional testing in cells suggest a model in which seipin oligomers initially detect forming LDs in the ER via HHs and subsequently act as membrane anchors to enable lipid transfer and LD growth.


Assuntos
Proteínas de Drosophila , Subunidades gama da Proteína de Ligação ao GTP , Gotículas Lipídicas , Modelos Biológicos , Modelos Moleculares , Animais , Microscopia Crioeletrônica , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Retículo Endoplasmático/química , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/ultraestrutura , Subunidades gama da Proteína de Ligação ao GTP/química , Subunidades gama da Proteína de Ligação ao GTP/genética , Subunidades gama da Proteína de Ligação ao GTP/metabolismo , Gotículas Lipídicas/metabolismo , Gotículas Lipídicas/ultraestrutura , Domínios Proteicos , Relação Estrutura-Atividade
17.
Structure ; 23(7): 1169-78, 2015 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-26027734

RESUMO

The human von Hippel-Lindau (VHL) tumor suppressor is a marginally stable protein previously used as a model substrate of eukaryotic refolding and degradation pathways. When expressed in the absence of its cofactors, VHL cannot fold and is quickly degraded by the quality control machinery of the cell. We combined computational methods with in vivo experiments to examine the basis of the misfolding propensity of VHL. By expressing a set of randomly mutated VHL sequences in yeast, we discovered a more stable mutant form. Subsequent modeling suggested the mutation had caused a conformational change affecting cofactor and chaperone interaction, and this hypothesis was then confirmed by additional knockout and overexpression experiments targeting a yeast cofactor homolog. These findings offer a detailed structural basis for the modulation of quality control fate in a model misfolded protein and highlight burial mode modeling as a rapid means to detect functionally important conformational changes in marginally stable globular domains.


Assuntos
Proteína Supressora de Tumor Von Hippel-Lindau/química , Sequência de Aminoácidos , Substituição de Aminoácidos , Estabilidade Enzimática , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Saccharomyces cerevisiae , Proteína Supressora de Tumor Von Hippel-Lindau/biossíntese , Proteína Supressora de Tumor Von Hippel-Lindau/genética
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