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1.
Elife ; 112022 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-35900198

RESUMO

Mimivirus is the prototype of the Mimiviridae family of giant dsDNA viruses. Little is known about the organization of the 1.2 Mb genome inside the membrane-limited nucleoid filling the ~0.5 µm icosahedral capsids. Cryo-electron microscopy, cryo-electron tomography, and proteomics revealed that it is encased into a ~30-nm diameter helical protein shell surprisingly composed of two GMC-type oxidoreductases, which also form the glycosylated fibrils decorating the capsid. The genome is arranged in 5- or 6-start left-handed super-helices, with each DNA-strand lining the central channel. This luminal channel of the nucleoprotein fiber is wide enough to accommodate oxidative stress proteins and RNA polymerase subunits identified by proteomics. Such elegant supramolecular organization would represent a remarkable evolutionary strategy for packaging and protecting the genome, in a state ready for immediate transcription upon unwinding in the host cytoplasm. The parsimonious use of the same protein in two unrelated substructures of the virion is unexpected for a giant virus with thousand genes at its disposal.


Assuntos
Vírus Gigantes , Mimiviridae , Capsídeo/metabolismo , Microscopia Crioeletrônica/métodos , Genoma Viral , Vírus Gigantes/genética , Mimiviridae/genética , Nucleoproteínas/genética , Nucleoproteínas/metabolismo , Oxirredutases/metabolismo
2.
Sci Adv ; 6(5): eaax8286, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32064340

RESUMO

Perforin-2 (MPEG1) is thought to enable the killing of invading microbes engulfed by macrophages and other phagocytes, forming pores in their membranes. Loss of perforin-2 renders individual phagocytes and whole organisms significantly more susceptible to bacterial pathogens. Here, we reveal the mechanism of perforin-2 activation and activity using atomic structures of pre-pore and pore assemblies, high-speed atomic force microscopy, and functional assays. Perforin-2 forms a pre-pore assembly in which its pore-forming domain points in the opposite direction to its membrane-targeting domain. Acidification then triggers pore formation, via a 180° conformational change. This novel and unexpected mechanism prevents premature bactericidal attack and may have played a key role in the evolution of all perforin family proteins.


Assuntos
Bactérias/imunologia , Evolução Molecular , Profilinas/ultraestrutura , Conformação Proteica , Animais , Bactérias/patogenicidade , Humanos , Imunidade Inata/imunologia , Macrófagos/química , Macrófagos/microbiologia , Mamíferos/microbiologia , Camundongos , Fagócitos/química , Fagócitos/microbiologia , Profilinas/química
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