RESUMO
Middle East respiratory syndrome is a severe respiratory illness caused by an infectious coronavirus. This virus is associated with a high mortality rate, but there is as of yet no effective vaccine or antibody available for human immunity/treatment. Drug design relies on understanding the 3D structures of viral proteins; however, arriving at such understanding is difficult for intrinsically disordered proteins, whose disorder-dependent functions are key to the virus's biology. Disorder is suggested to provide viral proteins with highly flexible structures and diverse functions that are utilized when invading host organisms and adjusting to new habitats. To date, the functional roles of intrinsically disordered proteins in the mechanisms of MERS-CoV pathogenesis, transmission, and treatment remain unclear. In this study, we performed structural analysis to evaluate the abundance of intrinsic disorder in the MERS-CoV proteome and in individual proteins derived from the MERS-CoV genome. Moreover, we detected disordered protein binding regions, namely, molecular recognition features and short linear motifs. Studying disordered proteins/regions in MERS-CoV could contribute to unlocking the complex riddles of viral infection, exploitation strategies, and drug development approaches in the near future by making it possible to target these important (yet challenging) unstructured regions.
Assuntos
Infecções por Coronavirus/virologia , Proteínas Intrinsicamente Desordenadas/química , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Proteínas não Estruturais Virais/química , Bases de Dados de Proteínas , Humanos , Domínios ProteicosRESUMO
Intrinsically disordered proteins/regions (IDPs/IDRs) fail to fold completely into 3D structures, but have major roles in determining protein function. While natively disordered proteins/regions have been found to fulfill a wide variety of primary cellular roles, the functions of many disordered proteins in numerous species remain to be uncovered. Here, we perform the first large-scale study of IDPs/IDRs in the genus Camelus, one of the most important mammalians in Asia and North Africa, in order to explore the biological roles of these proteins. The study includes the prediction of disordered proteins/regions in Camelus species and in humans using multiple state-of-the-art prediction tools. Additionally, we provide a comparative analysis of Camelus and Homo sapiens IDPs/IDRs for the sake of highlighting the distinctive use of disorder in each genus. Our findings indicate that the human proteome is more disordered than the Camelus proteome. Gene Ontology analysis also revealed that Camelus IDPs are enriched in glutathione catabolism and lactose biosynthesis.
Assuntos
Camelus , Genômica , Proteínas Intrinsicamente Desordenadas/genética , Animais , Biologia Computacional , Genoma , Humanos , Proteínas Intrinsicamente Desordenadas/química , Conformação Proteica , Proteoma/metabolismo , Proteômica , Especificidade da EspécieRESUMO
Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory illness in humans; the second-largest and most deadly outbreak to date occurred in Saudi Arabia. The dromedary camel is considered a possible host of the virus and also to act as a reservoir, transmitting the virus to humans. Here, we studied evolutionary relationships for 31 complete genomes of betacoronaviruses, including eight newly sequenced MERS-CoV genomes isolated from dromedary camels in Saudi Arabia. Through bioinformatics tools, we also used available sequences and 3D structure of MERS-CoV spike glycoprotein to predict MERS-CoV epitopes and assess antibody binding affinity. Phylogenetic analysis showed the eight new sequences have close relationships with existing strains detected in camels and humans in Arabian Gulf countries. The 2019-nCov strain appears to have higher homology to both bat coronavirus and SARS-CoV than to MERS-CoV strains. The spike protein tree exhibited clustering of MERS-CoV sequences similar to the complete genome tree, except for one sequence from Qatar (KF961222). B cell epitope analysis determined that the MERS-CoV spike protein has 24 total discontinuous regions from which just six epitopes were selected with score values of >80%. Our results suggest that the virus circulates by way of camels crossing the borders of Arabian Gulf countries. This study contributes to finding more effective vaccines in order to provide long-term protection against MERS-CoV and identifying neutralizing antibodies.
Assuntos
Camelus/virologia , Infecções por Coronavirus/virologia , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Glicoproteína da Espícula de Coronavírus/genética , Sequência de Aminoácidos , Animais , Betacoronavirus/classificação , Betacoronavirus/genética , Betacoronavirus/isolamento & purificação , Evolução Biológica , DNA Complementar/química , DNA Viral/química , Epitopos/análise , Epitopos/química , Epitopos/genética , Biblioteca Gênica , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/classificação , Coronavírus da Síndrome Respiratória do Oriente Médio/isolamento & purificação , Filogenia , RNA Viral/análise , RNA Viral/química , RNA Viral/isolamento & purificação , Arábia SauditaRESUMO
Camelus dromedarius has played a pivotal role in both culture and way of life in the Arabian peninsula, particularly in arid regions where other domestic animals cannot be easily domesticated. Although, the mitochondrial genomes have recently been sequenced for several camelid species, wider phylogenetic studies are yet to be performed. The features of conserved gene elements, rapid evolutionary rate, and rare recombination make the mitochondrial genome a useful molecular marker for phylogenetic studies of closely related species. Here we carried out a comparative analysis of previously sequenced mitochondrial genomes of camelids with an emphasis on C. dromedarius, revealing a number of noticeable findings. First, the arrangement of mitochondrial genes in C. dromedarius is similar to those of the other camelids. Second, multiple sequence alignment of intergenic regions shows up to 90% similarity across different kinds of camels, with dromedary camels to reach 99%. Third, we successfully identified the three domains (termination-associated sequence, conserved domain and conserved sequence block) of the control region structure. The phylogenetic tree analysis showed that C. dromedarius mitogenomes were significantly clustered in the same clade with Lama pacos mitogenome. These findings will enhance our understanding of the nucleotide composition and molecular evolution of the mitogenomes of the genus Camelus, and provide more data for comparative mitogenomics in the family Camelidae.