EMBO J. 2000 Oct 16;19(20):5324-31. Post-translational hydroxylation at the N-terminus of the prion protein reveals presence of PPII structure in vivo.
Gill AC, Ritchie MA, Hunt LG, Steane SE, Davies KG, Bocking SP, Rhie AG, Bennett AD, Hope J.
Institute for Animal Health, Compton, Newbury, Berkshire, RG20 7NN, UK.
The transmissible spongiform encephalopathies are characterized by conversion of a host protein, PrP(C) (cellular prion protein), to a protease-resistant isoform, PrP(Sc) (prion protein scrapie isoform). The importance of the highly flexible, N-terminal region of PrP has recently become more widely appreciated, particularly the biological activities associated with its metal ion-binding domain and its potential to form a poly(L-proline) II (PPII) helix. Circular dichroism spectroscopy of an N-terminal peptide, PrP(37-53), showed that the PPII helix is formed in aqueous buffer; as it also contains an Xaa-Pro-Gly consensus sequence, it may act as a substrate for the collagen-modifying enzyme prolyl 4-hydroxylase. Direct evidence for this modification was obtained by mass spectrometry and Edman sequencing in recombinant mouse PrP secreted from stably transfected Chinese hamster ovary cells. Almost complete conversion of proline to 4-hydroxyproline occurs specifically at residue Pro44 of this murine protein; the same hydroxylated residue was detected, at lower levels, in PrP(Sc) from the brains of scrapie-infected mice. Cation binding and/or post-translational hydroxylation of this region of PrP may regulate its role in the physiology and pathobiology of the cell.
PMID:_11032800
J Neurochem. 2000 Nov;75(5):1889-97. The cellular prion protein colocalizes with the dystroglycan complex in the brain.
Keshet GI, Bar-Peled O, Yaffe D, Nudel U, Gabizon R.
Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Hospital, Jerusalem, Israel.
The function of PrP(C), the cellular prion protein (PrP), is still unknown. Like other glycophosphatidylinositol-anchored proteins, PrP resides on Triton-insoluble, cholesterol-rich membranous microdomains, termed rafts. We have recently shown that the activity and subcellular localization of the neuronal isoform of nitric oxide synthase (nNOS) are impaired in adult PrP(0/0) mice as well as in scrapie-infected mice. In this study, we sought to determine whether PrP and nNOS are part of the same functional complex and, if so, to identify additional components of such a complex. To this aim, we looked for proteins that coimmunoprecipitated with PrP in the presence of detergents either that completely dissociate rafts, to identify stronger interactions, or that preserve the raft structure, to identify weaker interactions. Using this detergent-dependent immunoprecipitation protocol we found that PrP interacts strongly with dystroglycan, a transmembrane protein that is the core of the dystrophin-glycoprotein complex (DGC). Additional results suggest that PrP also interacts with additional members of the DGC, including nNOS. PrP coprecipitated only with established presynaptic proteins, consistent with recent findings suggesting that PrP is a presynaptic protein.
PMID:_11032878
Neurosci Lett. 2000 Nov 3;293(3):163-6. Attenuated Creutzfeldt-Jakob Disease agents can hide more virulent infections.
Manuelidis L, Yun Lu Z.
Section of Neuropathology, Yale Medical School 310 Cedar Street, New Haen, CT 06510, New Haven, USA. laura.manuelidiale.edu
We previously showed that a slow infectious strain of Creutzfeldt-Jakob Disease (CJD) can dramatically suppress the expression of a fast virulent agent injected intracerebrally 80days later. While the slow SY agent eventually produced disease at approximately 400days, there was little evidence of the fast FU agent. However, two of 18superinfected mice showed a minor increase in pathologic changes. To determine if FU was partially or completely suppressed, or if FU and SY agents formed a 'chimera' with intermediate incubation properties as predicted by prion theory, we passaged representative brains. All traces of FU were obliterated in typical brains of suppressed mice. The two aberrant mice however had mixed SY and FU infections, with FU reappearing at late stages of SY disease. Thus less virulent sporadic CJD infections in older people can conceal other agents such as variant CJD, the more recently evolved and virulent agent linked to bovine spongiform encephalopathy. This powerful model of agent-induced repression also implicates targets other than prion protein (PrP) in eliminating infection.
PMID:_11036186
Neurosci Lett. 2000 Nov 3;293(3):207-10. Caspase-3 activation by beta-amyloid and prion protein peptides is independent from their neurotoxic effect.
Saez-Valero J, Angeretti N, Forloni G.
Biology of Neurodegenerative Disorders, Istituto di Ricerche Farmacologiche 'Mario Negri Via Eritrea 62, 20157, Milan, Italy.
Synthetic peptides corresponding to residues 25-35 of beta-amyloid (beta 25-35) and 106-126 of prion protein (PrP 106-126) are amyloidogenic and cause neuronal death by apoptosis in vitro. We evaluated, in rat cortical neurons, the role of caspases activation in the peptides neurotoxicity by measuring of caspase-3 (CPP32) activity and applying a non-selective caspase inhibitor (z-VAD-fmk) or CPP32-specific inhibitor (Asp-Glu-Val-Asp-CHO (DEVD-CHO)). CPP32 was dose-dependently activated by both peptides (2.5-50 microM). The caspase inhibitors completely abolished the CPP32 activation induced by the peptides. However, the neurotoxic effect was partially attenuated with z-VAD-fmk, while no antagonism was found with DEVD-CHO. Thus, although beta 25-35 and PrP 106-126 robustly activated CPP32, their neurotoxic effect was independent of this caspase activation.
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