EMBO J. 2003 May 1;22(9):2071-81. Domain organization and structure-function relationship of the HET-s prion protein of Podospora anserina.
Balguerie A, Dos Reis S, Ritter C, Chaignepain S, Coulary-Salin B, Forge V, Bathany K, Lascu I, Schmitter JM, Riek R, Saupe SJ.
Laboratoire de Genetique Moleculaire des Champignons, Service de Microscopie, UMR 5095 CNRS/Universite de Bordeaux 2, 1 rue Camille St Saens, 33077 Bordeaux cedex, France.
The [Het-s] infectious element of the fungus Podospora anserina is a prion protein involved in a genetically controlled cell death reaction termed heterokaryon incompatibility. Previous analyses indicate that [Het-s] propagates as a self-perpetuating amyloid aggregate. The HET-s protein is 289 amino acids in length. Herein, we identify the region of the HET-s protein that is responsible for amyloid formation and prion propagation. The region of HET-s spanning residues 218-289 forms amyloid fibers in vitro and allows prion propagation in vivo. Conversely, a C-terminal deletion in HET-s prevents amyloid aggregation in vitro and prion propagation in vivo, and abolishes the incompatibility function. In the soluble form of HET-s, the region from residue 1 to 227 forms a well-folded domain while the C-terminal region is highly flexible. Together, our data establish a domain structure-function relationship for HET-s amyloid formation, prion propagation and incompatibility activity.
PMID:_12727874
J Biol Chem. 2003 May 5 [Epub ahead of print]. Prion or amyloid-b-derived Cu(II)- or free Zn(II)-ions support S-nitroso-dependent autocleavage of glypican-1 heparan sulfate.
Mani K, Cheng F, Havsmark B, Jonsson M, Belting M, Fransson LA.
Department of Cell and Molecular Biology, Lund University, Lund S-221 84.
Copper-ions are generally bound to proteins, e.g. the prion and the amyloid beta proteins. We have previously shown that copper-ions are required to nitrosylate thiol groups in the core protein of glypican-1, a heparan sulfate-substituted proteoglycan. When S-nitrosylated glypican-1 is then exposed to an appropriate reducing agent, such as ascorbate, nitric oxide is released and autocatalyzes deaminative cleavage of the glypican-1 heparan sulfate side-chains at sites where the glucosamines are N-unsubstituted. These processes take place in a step-wise manner while glypican-1 recycles via a caveolin-1-associated pathway where copper-ions could be provided by the prion protein. Here we show, by using both biochemical and microscopic techniques, that (a) the glypican-1 core protein binds copper(II) ions, reduces them to copper(I) when the thiols are nitrosylated and reoxidizes copper(I) to copper(II) when ascorbate releases nitric oxide, (b) maximally S-nitrosylated glypican-1 can cleave its own heparan sulfate chains at all available sites in a nitroxyl ion-dependent reaction, (c) free zinc(II) ions, which are redox-inert, also support autocleavage of glypican-1 heparan sulfate, probably via transnitrosation, while they inhibit copper(II)-supported degradation, and (d) copper(II)-loaded, but not zinc(II)-loaded, prion protein or amyloid beta peptide support heparan sulfate degradation. As glypican-1 in prion null cells is poorly S-nitrosylated and as ectopic expression of cellular prion protein restores S-nitrosylation of glypican-1 in these cells, we propose that one function of the cellular prion protein is to deliver copper(II) for the S-nitrosylation of recycling glypican-1.
PMID:_12732622 [PubMed - as supplied by publisher]
Proc Natl Acad Sci U S A. 2003 May 13;100(10):6093-7. Epub 2003 May 05. Ultra-high-pressure inactivation of prion infectivity in processed meat: a practical method to prevent human infection.
Brown P, Meyer R, Cardone F, Pocchiari M.
National Institutes of Health, Bethesda, MD 20892, USA. browninds.nih.gov
Bovine spongiform encephalopathy contamination of the human food chain most likely resulted from nervous system tissue in mechanically recovered meat used in the manufacture of processed meats. We spiked hot dogs with 263K hamster-adapted scrapie brain (10% wtwt) to produce an infectivity level of approximately 9 log(10) mean lethal doses (LD(50)) per g of paste homogenate. Aliquots were subjected to short pressure pulses of 690, 1,000, and 1,200 MPa at running temperatures of 121-137 degrees C. Western blots of PrPres were found to be useful indicators of infectivity levels, which at all tested pressures were significantly reduced as compared with untreated controls: from approximately 10(3) LD(50) per g at 690 MPa to approximately 10(6) LD(50) per g at 1,200 MPa. The application of commercially practical conditions of temperature and pressure could ensure the safety of processed meats from bovine spongiform encephalopathy contamination, and could also be used to study phase transitions of the prion protein from its normal to misfolded state.
PMID:_12732724
Transfus Clin Biol. 1999 Feb;6(1):17-23. A crucial role for B cells in neuroinvasive scrapie.
Brandner S, Klein MA, Aguzzi A.
Institute of Neuropathology, University of Zurich, Switzerland.
Although prions are most efficiently propagated via intracerebral inoculation, peripheral administration has caused kuru [Gajdusek et al, 1966], iatrogenic Creutzfeldt-Jakob disease (CJD) [Gibbs et al, 1997], bovine spongiform encephalitis (BSE), and new variant CJD [Hill et al, 1997; Bruce et al, 1997]. Neurological disease after peripheral inoculation depends on prion expansion within cells of the lymphoreticular system (LRS) [Lasmezas et al. 1996; Wilesmith et al, 1992]. In order to identify the nature of the latter cells, we inoculated a panel of immune deficient mice with prions intraperitoneally. While defects affecting only T lymphocytes had no apparent effect, all mutations affecting differentiation and responses of B lymphocytes prevented development of clinical scrapie. Since absence of B cells and of antibodies correlates with severe defects in follicular dendritic cells (FDCs), the lack of any of these three components may prevent clinical scrapie. Yet, mice expressing immunoglobulins exclusively of the M subclass without detectable specificity for PrPc, and mice with differentiated B cells but lacking functional FDCs, developed scrapie after peripheral inoculation: therefore, differentiated B cells appear to play a crucial role in neuroinvasion of scrapie regardless of B-cell receptor specificity.
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