All other conserved residues from the DFG-motif and the RD-motif have a similar conformation to the corresponding residues of PKA, as clearly seen in November Structure of NTD RSK novel bB-sheet

ript. Competing Interests: The authors have declared that no competing interests exist. E-mail: [email protected]; 18055761 [email protected] Introduction Transmissible spongiform encephalopathies or prion diseases are a group of invariably fatal neurodegenerative disorders associated with misfolded conformers of the normal cellular prion protein. In animals the disease occurs naturally as scrapie in sheep, bovine spongiform encephalopathy in cattle and chronic wasting disease in deer and elk. In humans the disease occurs in sporadic, familial and acquired forms with phenotypes including Creutzfeldt-Jakob Disease, Gerstmann-Straussler-Scheinker syndrome and Fatal Familial Insomnia. The transmissible nature of prion disease has been attributed to the template directed misfolding of PrPC, which is supported by the absolute requirement of PrPC expression for disease transmission and pathogenesis. The protein only hypothesis proposes that PrPSc is the principal 3544-24-9 component of this infectious agent or template. However, it is not clear whether PrPSc is the only component of the infectious and/or pathogenic entity. Cell-free models of template directed PrPC misfolding have demonstrated that PrPSc can induce a conformational change in PrPC, rendering it protease resistant and infectious under prescribed conditions. Previously, the efficiency of this process using partially purified constituents has been low, often requiring a large excess of PrPSc, which has been proposed to reflect the need for a catalytic co-factor in the process. This view is further supported by the low levels 11325787 of infectivity produced by folding recombinant PrP into a protease resistant form, although this may also reflect the absence of post-translational modification of the recombinant protein and the nature of the transgenic mouse model used in the bioassay. The reported ability of polyanions to stimulate the misfolding of partially purified mammalian or recombinant PrPC and generate August 2010 | Volume 5 | Issue 8 | e12351 Prion Protein Misfolding infectivity in the absence of an initiating PrPSc seed provides compelling evidence for the role of a cofactor for the acquisition of prion infectivity. Negatively charged macromolecules or polyanions, including nucleic acids, phospholipids and glycosaminoglycans have been implicated as facilitating cofactors in the conversion of PrPC to PrPSc and thereby in the transmission and pathogenesis of prion disease. Mechanistically, GAGs have been proposed to act as scaffolds to support the misfolding of PrPC. Further, GAGs have been reported to act as receptors for PrPSc on the cell surface, affect PrPC trafficking and are also found in PrPSc associated plaques. Treatments, which modify the GAG content of prion infected cells, or treatment of infected cells with GAGs have been shown to clear prion infection. Pentosan polysulphate, a heparan sulphate mimetic, can prolong incubation time in prion infected mice and is currently being used on a compassionate basis in variant CJD. Significantly, unlike RNA, GAGs are found at the cell surface and along the endosomal pathway where PrPSc formation has been proposed to occur. Whilst the ability of polyanions to stimulate PrPres formation in cell-free assays and from recombinant PrP appears to be species independent, PrPres formation following the specific depletion of polyanions from the PrPC substrate appears to be host species specific. Using a cell-free model to investigate reaction condit

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