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The Structural Architecture of an Infectious Mammalian Prion Using Electron Cryomicroscopy
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نویسنده
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vázquez-fernández e. ,vos m.r. ,afanasyev p. ,cebey l. ,sevillano a.m. ,vidal e. ,rosa i. ,renault l. ,ramos a. ,peters p.j. ,fernández j.j. ,van heel m. ,young h.s. ,requena j.r. ,wille h.
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منبع
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plos pathogens - 2016 - دوره : 12 - شماره : 9
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چکیده
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The structure of the infectious prion protein (prpsc),which is responsible for creutzfeldt-jakob disease in humans and bovine spongiform encephalopathy,has escaped all attempts at elucidation due to its insolubility and propensity to aggregate. prpsc replicates by converting the non-infectious,cellular prion protein (prpc) into the misfolded,infectious conformer through an unknown mechanism. prpsc and its n-terminally truncated variant,prp 27–30,aggregate into amorphous aggregates,2d crystals,and amyloid fibrils. the structure of these infectious conformers is essential to understanding prion replication and the development of structure-based therapeutic interventions. here we used the repetitive organization inherent to gpi-anchorless prp 27–30 amyloid fibrils to analyze their structure via electron cryomicroscopy. fourier-transform analyses of averaged fibril segments indicate a repeating unit of 19.1 å. 3d reconstructions of these fibrils revealed two distinct protofilaments,and,together with a molecular volume of 18,990 å3,predicted the height of each prp 27–30 molecule as ~17.7 å. together,the data indicate a four-rung β-solenoid structure as a key feature for the architecture of infectious mammalian prions. furthermore,they allow to formulate a molecular mechanism for the replication of prions. knowledge of the prion structure will provide important insights into the self-propagation mechanisms of protein misfolding. © 2016 vázquez-fernández et al.
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آدرس
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department of biochemistry,university of alberta,edmonton,ab,canada,centre for prions and protein folding diseases,university of alberta,edmonton,ab, Canada, fei company,nanoport europe,eindhoven, Netherlands, institute of biology leiden,necen,leiden,netherlands,the maastricht multimodal molecular imaging institute,maastricht university,maastricht, Netherlands, department of biochemistry,university of alberta,edmonton,ab,canada,centre for prions and protein folding diseases,university of alberta,edmonton,ab, Canada, cimus biomedical research institute university of santiago de compostela-idis,santiago de compostela, Spain, irta,centre de recerca en sanitat animal (cresa,irta-uab),campus de la universitat autònoma de barcelona,bellaterra,catalonia, Spain, cimus biomedical research institute university of santiago de compostela-idis,santiago de compostela, Spain, department of biochemistry,university of alberta,edmonton,ab,canada,institute of biology leiden,necen,leiden, Netherlands, cimus biomedical research institute university of santiago de compostela-idis,santiago de compostela,spain,department of psychiatry and behavioral sciences,the johns hopkins university school of medicine,baltimore,md, United States, the maastricht multimodal molecular imaging institute,maastricht university,maastricht, Netherlands, centro nacional de biotecnologia - csic,campus universidad autónoma,madrid, Spain, institute of biology leiden,necen,leiden,netherlands,brazilian nanotechnology national laboratory - lnnano,cnpem,campinas,são paulo,brazil,faculty of natural science,imperial college london,london, United Kingdom, department of biochemistry,university of alberta,edmonton,ab, Canada, cimus biomedical research institute university of santiago de compostela-idis,santiago de compostela, Spain, department of biochemistry,university of alberta,edmonton,ab,canada,centre for prions and protein folding diseases,university of alberta,edmonton,ab, Canada
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Authors
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