New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein (original) (raw)
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Soluble Dimeric Prion Protein Binds PrPSc In Vivo and Antagonizes Prion Disease
Cell, 2003
and familial human transmissible spongiform encephalopathies (TSEs) exhibit mutations of Prnp (Hsiao et al., 1 Institute of Neuropathology, Schmelzbergstrasse University Hospital of Zü rich 1989). PrP C is encoded by a single exon of the Prnp gene 2 Institute of Laboratory Animal Science Sternwartstrasse and is anchored to the cell surface by a glycosyl phosphatidyl inositol (GPI) residue. Its physiological function University of Zü rich CH-8091 Zü rich is still poorly understood (Behrens and Aguzzi, 2002). A soluble form of PrP C lacking the glycolipid moiety is Switzerland 3 Institute of Animal Neurology present in serum (Lopez et al., 1990; Perini et al., 1996; Tagliavini et al., 1992) and epididymal fluid (Gatti et al., University of Bern Bremgartenstr. 109a 2002). In primary cultures of splenocytes and cerebellar granule cells, a substantial amount of PrP C is shed after CH-3012 Bern Switzerland loss of the GPI anchor (Parizek et al., 2001).
Journal of Virology, 2015
ABSTRACTMammalian prions are proteinaceous infectious agents composed of misfolded assemblies of the host-encoded, cellular prion protein (PrP). Physiologically, the N-terminal polybasic region of residues 23 to 31 of PrP has been shown to be involved in its endocytic trafficking and interactions with glycosaminoglycans or putative ectodomains of membrane-associated proteins. Several recent reports also describe this PrP region as important for the toxicity of mutant prion proteins and the efficiency of prion propagation, bothin vitroandin vivo. The question remains as to whether the latter observations made with mouse PrP and mouse prions would be relevant to other PrP species/prion strain combinations given the dramatic impact on prion susceptibility of minimal amino acid substitutions and structural variations in PrP. Here, we report that transgenic mouse lines expressing ovine PrP with a deletion of residues 23 to 26 (KKRP) or mutated in this N-terminal region (KQHPH instead of ...
The role of the prion protein in neurodegenerative disorders
2013
evidenziato che il trattamento acuto dei neuroni con tali oligomeri altera la regolazione della PrP C sul SOCE e su Fyn e l'ingresso di Ca 2+ nel mitocondrio a seguito dell'attivazione dei recettori ionotropici del glutammato. Questi dati suggeriscono pertanto l'esistenza di un meccanismo PrP C-dipendente che causa dis-omeostasi neuronale del Ca 2+ indotta dal peptide Aβ. X and, most remarkably, the capacity to self-propagate into host organisms through an auto-catalytic mechanism in which pre-formed PrP Sc promote the PrP C-PrP Sc conversion. Much data has been accumulated over the years to support the "protein only" hypothesis, including other "unorthodox" prion aspects. One of these is the observation that PrP Sc can give rise to different disease phenotypes that are faithfully propagated (Bruce and Fraser, 1991), which suggests the existence of prion strains distinguishable by hystopathological features, biochemical and physico-chemical properties, and by the incubation period of the disease. Recently, it was demonstrated modification in the circadian sleep rhythm (Collinge et al., 1994; Sakaguchi et al., 1996). The polypeptide coded by Prnp is subjected to several post-translational modifications: removal of the N-terminal signal peptide (aa 1-22), and of approximately 20 aa at the C-terminus (aa 231-253) to allow the GPI attachement (Stahl et al., 1990); the N-glycosilation at two asparagine residues (Asn181, 197) in the endoplasmic reticulum (ER); removal of mannose residues and addition of complex oligosaccharidic chains in the Golgi apparatus (Fig. 2). sheets (Fig. 3), which is further stabilized by a single disulfide bond (Riek et al., 1996; Zahn et al., 2000). The N-terminal contains five repetitions of eight aa (PHGGGWGQ) (octarepeats, OR) that can coordinate up-to six Cu 2+ (Brown et al., 1997). A hydrophobic region, located between the OR and the first α-helix (aa 106-126) is considered a possible trans-membrane domain, and exerts neurotoxic functions (Forloni et al., 1993). moiety. Like other GPI-anchored proteins, PrP C is located to sphingolipid-and cholesterol-abundant microdomains, known as detergent-resistant patches, or lipid rafts (Simons and Toomre, 2000), which many studies indicate as putative centres for signal transduction events. It remains to be tested whether the GPI-anchoring modulates other biological properties of PrP C , as shown for the fibroblast GPI-growth factor (Kohl et al., 2002). Sc (right). The α-helical and β-strand regions are shown in green and blue, respectively. It is to be noted the PrP Sc enrichement in the β-sheet content
Identification of proteins with high affinity for refolded and native PrPC
PROTEOMICS, 2006
PrP C , the cellular prion protein, is widely expressed in most tissues, including brain, muscle and the gastrointestinal tract, but its physiological role remains unclear. During propagation of transmissible spongiform encephalopathies (TSEs), prion protein is converted to the pathological isoform, PrP Sc , in a process believed to be mediated by as-yet-unknown host factors. The identification of proteins associated with PrP may provide information about the biology of prions and the pathogenesis of TSEs. In the present work, we report proteins identified from brain tissue based on their ability to bind to recombinant PrP (recPrP) or form multimolecular complexes with native PrP C in the presence of cross-linkers. Immobilized his-tagged recPrP was used as an affinity matrix to isolate PrP-interacting proteins from brain homogenates of normal individuals. In parallel, PrP C-associated proteins were characterized by cross-linking and coimmunoprecipitation assays. The unknown molecules were identified by MS and the results of LC-MS/MS analysis were subsequently verified by Western blot. Both techniques resulted in identification of proteins participating in the formation of cytoskeleton and signal transduction, further supporting the hypothesis that PrP is involved in the organization and function of receptors throughout the nervous system.