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1.
Nature ; 565(7739): 377-381, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30626974

RESUMO

To initiate infection, many viruses enter their host cells by triggering endocytosis following receptor engagement. However, the mechanisms by which non-enveloped viruses escape the endosome are poorly understood. Here we present near-atomic-resolution cryo-electron microscopy structures for feline calicivirus both undecorated and labelled with a soluble fragment of its cellular receptor, feline junctional adhesion molecule A. We show that VP2, a minor capsid protein encoded by all caliciviruses1,2, forms a large portal-like assembly at a unique three-fold axis of symmetry, following receptor engagement. This assembly-which was not detected in undecorated virions-is formed of twelve copies of VP2, arranged with their hydrophobic N termini pointing away from the virion surface. Local rearrangement at the portal site leads to the opening of a pore in the capsid shell. We hypothesize that the portal-like assembly functions as a channel for the delivery of the calicivirus genome, through the endosomal membrane, into the cytoplasm of a host cell, thereby initiating infection. VP2 was previously known to be critical for the production of infectious virus3; our findings provide insights into its structure and function that advance our understanding of the Caliciviridae.


Assuntos
Calicivirus Felino/metabolismo , Calicivirus Felino/ultraestrutura , Proteínas do Capsídeo/metabolismo , Proteínas do Capsídeo/ultraestrutura , Microscopia Crioeletrônica , Molécula A de Adesão Juncional/ultraestrutura , Receptores Virais/ultraestrutura , Montagem de Vírus , Animais , Calicivirus Felino/química , Calicivirus Felino/crescimento & desenvolvimento , Proteínas do Capsídeo/química , Gatos , Linhagem Celular , Endossomos/metabolismo , Endossomos/virologia , Genoma Viral , Interações Hidrofóbicas e Hidrofílicas , Molécula A de Adesão Juncional/química , Molécula A de Adesão Juncional/metabolismo , Modelos Moleculares , Receptores Virais/química , Receptores Virais/metabolismo , Eletricidade Estática , Vírion/química , Vírion/genética , Vírion/metabolismo , Vírion/ultraestrutura
2.
PLoS One ; 19(3): e0291892, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38483913

RESUMO

Genomic surveillance is crucial for tracking emergence and spread of novel variants of pathogens, such as SARS-CoV-2, to inform public health interventions and to enforce control measures. However, in some settings especially in low- and middle- income counties, where sequencing platforms are limited, only certain patients get to be selected for sequencing surveillance. Here, we show that patients with multiple comorbidities potentially harbour SARS-CoV-2 with higher mutation rates and thus deserve more attention for genomic surveillance. The relationship between the patient comorbidities, and type of amino acid mutations was assessed. Correlation analysis showed that there was a significant tendency for mutations to occur within the ORF1a region for patients with higher number of comorbidities. Frequency analysis of the amino acid substitution within ORF1a showed that nsp3 P822L of the PLpro protease was one of the highest occurring mutations. Using molecular dynamics, we simulated that the P822L mutation in PLpro represents a system with lower Root Mean Square Deviation (RMSD) fluctuations, and consistent Radius of gyration (Rg), Solvent Accessible Surface Area (SASA) values-indicate a much stabler protein than the wildtype. The outcome of this study will help determine the relationship between the clinical status of a patient and the mutations of the infecting SARS-CoV-2 virus.


Assuntos
COVID-19 , Taxa de Mutação , Humanos , SARS-CoV-2/genética , COVID-19/epidemiologia , COVID-19/genética , Mutação , Substituição de Aminoácidos , Simulação de Dinâmica Molecular
3.
Nutrients ; 15(3)2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36771440

RESUMO

The circadian system in the human body responds to daily environmental changes to optimise behaviour according to the biological clock and also influences various physiological processes. The suprachiasmatic nuclei are located in the anterior hypothalamus of the brain, and they synchronise to the 24 h light/dark cycle. Human physiological functions are highly dependent on the regulation of the internal circadian clock. Skeletal muscles comprise the largest collection of peripheral clocks in the human body. Both central and peripheral clocks regulate the interaction between the musculoskeletal system and energy metabolism. The skeletal muscle circadian clock plays a vital role in lipid and glucose metabolism. The pathogenesis of osteoporosis is related to an alteration in the circadian rhythm. In the present review, we discuss the disturbance of the circadian rhythm and its resultant effect on the musculoskeletal system. We also discuss the nutritional strategies that are potentially effective in maintaining the system's homeostasis. Active collaborations between nutritionists and physiologists in the field of chronobiological and chrononutrition will further clarify these interactions. This review may be necessary for successful interventions in reducing morbidity and mortality resulting from musculoskeletal disturbances.


Assuntos
Relógios Circadianos , Sistema Musculoesquelético , Humanos , Ritmo Circadiano/fisiologia , Relógios Circadianos/fisiologia , Fotoperíodo , Metabolismo Energético/fisiologia
4.
Acta Crystallogr F Struct Biol Commun ; 76(Pt 9): 414-421, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32880589

RESUMO

The bifunctional alcohol/aldehyde dehydrogenase (AdhE) comprises both an N-terminal aldehyde dehydrogenase (AldDH) and a C-terminal alcohol dehydrogenase (ADH). In vivo, full-length AdhE oligomerizes into long oligomers known as spirosomes. However, structural analysis of AdhE is challenging owing to the heterogeneity of the spirosomes. Therefore, the domains of AdhE are best characterized separately. Here, the structure of ADH from the pathogenic Escherichia coli O157:H7 was determined to 1.65 Šresolution. The dimeric crystal structure was confirmed in solution by small-angle X-ray scattering.


Assuntos
Álcool Desidrogenase/química , Aldeído Oxirredutases/química , Escherichia coli O157/enzimologia , Proteínas de Escherichia coli/química , Ferro/química , NAD/química , Subunidades Proteicas/química , Álcool Desidrogenase/genética , Álcool Desidrogenase/metabolismo , Aldeído Oxirredutases/genética , Aldeído Oxirredutases/metabolismo , Sequência de Aminoácidos , Domínio Catalítico , Cátions Bivalentes , Clonagem Molecular , Cristalografia por Raios X , Escherichia coli O157/genética , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Ferro/metabolismo , Modelos Moleculares , NAD/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
5.
Nat Commun ; 10(1): 4527, 2019 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-31586059

RESUMO

Aldehyde-alcohol dehydrogenase (AdhE) is a key enzyme in bacterial fermentation, converting acetyl-CoA to ethanol, via two consecutive catalytic reactions. Here, we present a 3.5 Å resolution cryo-EM structure of full-length AdhE revealing a high-order spirosome architecture. The structure shows that the aldehyde dehydrogenase (ALDH) and alcohol dehydrogenase (ADH) active sites reside at the outer surface and the inner surface of the spirosome respectively, thus topologically separating these two activities. Furthermore, mutations disrupting the helical structure abrogate enzymatic activity, implying that formation of the spirosome structure is critical for AdhE activity. In addition, we show that this spirosome structure undergoes conformational change in the presence of cofactors. This work presents the atomic resolution structure of AdhE and suggests that the high-order helical structure regulates its enzymatic activity.


Assuntos
Álcool Desidrogenase/ultraestrutura , Aldeído Oxirredutases/ultraestrutura , Proteínas de Escherichia coli/ultraestrutura , Acetilcoenzima A/química , Álcool Desidrogenase/isolamento & purificação , Álcool Desidrogenase/metabolismo , Aldeído Oxirredutases/isolamento & purificação , Aldeído Oxirredutases/metabolismo , Microscopia Crioeletrônica , Ensaios Enzimáticos , Proteínas de Escherichia coli/isolamento & purificação , Proteínas de Escherichia coli/metabolismo , Etanol/química , Mutação , Conformação Proteica em alfa-Hélice/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/ultraestrutura
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