Mammalian prions propagate as distinct strains and are composed of multichain assemblies of misfolded host-encoded prion protein (PrP). Here, we present a near-atomic resolution cryo-EM structure of PrP fibrils present in highly infectious prion rod preparations isolated from the brains of RML prion-infected mice. We found that prion rods comprise single-protofilament helical amyloid fibrils that coexist with twisted pairs of the same protofilaments. Each rung of the protofilament is formed by a single PrP monomer with the ordered core comprising PrP residues 94-225, which folds to create two asymmetric lobes with the N-linked glycans and the glycosylphosphatidylinositol anchor projecting from the C-terminal lobe. The overall architecture is comparable to that of recently reported PrP fibrils isolated from the brain of hamsters infected with the 263K prion strain. However, there are marked conformational variations that could result from differences in PrP sequence and/or represent distinguishing features of the distinct prion strains.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9279362 | PMC |
| http://dx.doi.org/10.1038/s41467-022-30457-7 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Structural and functional dynamics of human cone cGMP-phosphodiesterase important for photopic vision.
Proc Natl Acad Sci U S A
January 2025
Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242.
Cone cGMP-phosphodiesterase (PDE6) is the key effector enzyme for daylight vision, and its properties are critical for shaping distinct physiology of cone photoreceptors. We determined the structures of human cone PDE6C in various liganded states by single-particle cryo-EM that reveal essential functional dynamics and adaptations of the enzyme. Our analysis exposed the dynamic nature of PDE6C association with its regulatory γ-subunit (Pγ) which allows openings of the catalytic pocket in the absence of phototransduction signaling, thereby controlling photoreceptor noise and sensitivity.
View Article and Find Full Text PDFTamsulosin ameliorates bone loss by inhibiting the release of Cl through wedging into an allosteric site of TMEM16A.
Proc Natl Acad Sci U S A
January 2025
National Key Laboratory of Space Medicine, China Astronaut Research and Training Center, Beijing 100094, China.
TMEM16A, a key calcium-activated chloride channel, is crucial for many physiological and pathological processes such as cancer, hypertension, and osteoporosis, etc. However, the regulatory mechanism of TMEM16A is poorly understood, limiting the discovery of effective modulators. Here, we unveil an allosteric gating mechanism by presenting a high-resolution cryo-EM structure of TMEM16A in complex with a channel inhibitor that we identified, Tamsulosin, which is resolved at 2.
View Article and Find Full Text PDFMolecular basis of Spns1-mediated lysophospholipid transport from the lysosome.
Proc Natl Acad Sci U S A
January 2025
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Spns1 mediates the rate-limiting efflux of lysophospholipids from the lysosome to the cytosol. Deficiency of Spns1 is associated with embryonic senescence, as well as liver and skeletal muscle atrophy in animal models. However, the mechanisms by which Spns1 transports lysophospholipid and proton sensing remain unclear.
View Article and Find Full Text PDFX-Ray Crystallography of Viruses.
Subcell Biochem
December 2024
ALBA Synchrotron Light Source, Cerdanyola del Vallès, Spain.
Since the 1970s and for about 40 years, X-ray crystallography has been by far the most powerful approach for determining virus structures at close to atomic resolutions. Information provided by these studies has deeply and extensively enriched and shaped our vision of the virus world. In turn, the ever-increasing complexity and size of the virus structures being investigated have constituted a major driving force for methodological and conceptual developments in X-ray macromolecular crystallography (MX).
View Article and Find Full Text PDFConventional Electron Microscopy, Cryogenic Electron Microscopy, and Cryogenic Electron Tomography of Viruses.
Subcell Biochem
December 2024
School of Biomedical Sciences, The University of New South Wales, Sydney, NSW, Australia.
Electron microscopy (EM) techniques have been crucial for understanding the structure of biological specimens such as cells, tissues and macromolecular assemblies. Viruses and related viral assemblies are ideal targets for structural studies that help to define essential biological functions. Whereas conventional EM methods use chemical fixation, dehydration, and staining of the specimens, cryogenic electron microscopy (cryo-EM) preserves the native hydrated state.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!