RESUMEN
We modeled 3D structures of all SARS-CoV-2 proteins, generating 2,060 models that span 69% of the viral proteome and provide details not available elsewhere. We found that Ë6% of the proteome mimicked human proteins, while Ë7% was implicated in hijacking mechanisms that reverse post-translational modifications, block host translation, and disable host defenses; a further Ë29% self-assembled into heteromeric states that provided insight into how the viral replication and translation complex forms. To make these 3D models more accessible, we devised a structural coverage map, a novel visualization method to show what is-and is not-known about the 3D structure of the viral proteome. We integrated the coverage map into an accompanying online resource (https://aquaria.ws/covid) that can be used to find and explore models corresponding to the 79 structural states identified in this work. The resulting Aquaria-COVID resource helps scientists use emerging structural data to understand the mechanisms underlying coronavirus infection and draws attention to the 31% of the viral proteome that remains structurally unknown or dark.
Asunto(s)
Enzima Convertidora de Angiotensina 2/metabolismo , Interacciones Huésped-Patógeno/genética , Procesamiento Proteico-Postraduccional , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Sistemas de Transporte de Aminoácidos Neutros/química , Sistemas de Transporte de Aminoácidos Neutros/genética , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Enzima Convertidora de Angiotensina 2/química , Enzima Convertidora de Angiotensina 2/genética , Sitios de Unión , COVID-19/genética , COVID-19/metabolismo , COVID-19/virología , Biología Computacional/métodos , Proteínas de la Envoltura de Coronavirus/química , Proteínas de la Envoltura de Coronavirus/genética , Proteínas de la Envoltura de Coronavirus/metabolismo , Proteínas de la Nucleocápside de Coronavirus/química , Proteínas de la Nucleocápside de Coronavirus/genética , Proteínas de la Nucleocápside de Coronavirus/metabolismo , Humanos , Proteínas de Transporte de Membrana Mitocondrial/química , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Modelos Moleculares , Imitación Molecular , Neuropilina-1/química , Neuropilina-1/genética , Neuropilina-1/metabolismo , Fosfoproteínas/química , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Mapeo de Interacción de Proteínas/métodos , Multimerización de Proteína , SARS-CoV-2/química , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Proteínas de la Matriz Viral/química , Proteínas de la Matriz Viral/genética , Proteínas de la Matriz Viral/metabolismo , Proteínas Viroporinas/química , Proteínas Viroporinas/genética , Proteínas Viroporinas/metabolismo , Replicación ViralRESUMEN
Basal breast cancer is associated with younger age, early relapse, and a high mortality rate. Here, we use unbiased droplet-based single-cell RNA sequencing (RNA-seq) to elucidate the cellular basis of tumor progression during the specification of the basal breast cancer subtype from the luminal progenitor population in the MMTV-PyMT (mouse mammary tumor virus-polyoma middle tumor-antigen) mammary tumor model. We find that basal-like cancer cells resemble the alveolar lineage that is specified upon pregnancy and encompass the acquisition of an aberrant post-lactation developmental program of involution that triggers remodeling of the tumor microenvironment and metastatic dissemination. This involution mimicry is characterized by a highly interactive multicellular network, with involution cancer-associated fibroblasts playing a pivotal role in extracellular matrix remodeling and immunosuppression. Our results may partially explain the increased risk and poor prognosis of breast cancer associated with childbirth.
Asunto(s)
Fibroblastos Asociados al Cáncer/metabolismo , Carcinoma Basocelular/genética , Glándulas Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/genética , Transcriptoma , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Fibroblastos Asociados al Cáncer/patología , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/patología , Linaje de la Célula/genética , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Cadena alfa 1 del Colágeno Tipo I/genética , Cadena alfa 1 del Colágeno Tipo I/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Glándulas Mamarias Animales/patología , Glándulas Mamarias Animales/virología , Neoplasias Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/patología , Virus del Tumor Mamario del Ratón/crecimiento & desarrollo , Virus del Tumor Mamario del Ratón/patogenicidad , Metaloproteinasa 3 de la Matriz/genética , Metaloproteinasa 3 de la Matriz/metabolismo , Ratones , Metástasis de la Neoplasia , Embarazo , Análisis de la Célula Individual , Microambiente Tumoral/genéticaRESUMEN
Familial adult myoclonic epilepsy 1 (FAME1), first recognised in Japanese families, was recently shown to be caused by a TTTCA repeat insertion in intron 4 of SAMD12 on chromosome 8. We performed whole genome sequencing on two families with FAME, one of Sri Lankan origin and the other of Indian origin, and identified a TTTCA repeat insertion in SAMD12 in both families. Haplotype analysis revealed that both families shared the same core ancestral haplotype reported in Japanese and Chinese families with FAME1. Mutation dating, based on the length of shared haplotypes, estimated the age of the ancestral haplotype to be ~670 generations, or 17,000 years old. Our data extend the geographic range of this repeat expansion to Southern Asia and potentially implicate an even broader regional distribution given the age of the variant. This finding suggests patients of Asian ancestry with suspected FAME should be screened for the SAMD12 TTTCA expansion.
