Biophys Chem. 2003 May 1;104(1):79-94. Molecular dynamics simulation of the unfolding of the human prion protein domain under low pH and high temperature conditions.
Gu W, Wang T, Zhu J, Shi Y, Liu H.
Key Laboratory of Structural Biology, University of Science and Technology of China, Chinese Academy of Sciences, School of Life Sciences, Hefei, Anhui 230026, PR China.
Four 10-ns molecular dynamics (MD) simulations of the human prion protein domain (HuPrP 125-228) in explicit water solution have been performed. Each of the simulations mimicked a different environment of the protein: the neutral pH environment was simulated with all histidine residues neutral and bearing a ND proton and with other titratable side chains charged, the weakly acidic environment was simulated with all titratable side chains charged, the strongly acidic environment was simulated with all titratable side chains protonated. The protein in neutral pH environment was simulated at both ambient (298 K) and higher (350 K) temperatures. The native fold is stable in the neutral pH/ambient temperature simulation. Through out all other simulations, a quite stable core consisted of 10-20 residues around the disulfide bond retain their initial conformations. However, the secondary structures of the protein show changes of various degrees compared to the native fold, parts of the helices unfolded and the beta-sheets extended. Our simulations indicated that the heat-induced unfolding and acid-induced unfolding of HuPrP might follow different pathways: the initial stage of the acid-induced unfolding may include not only changes in secondary structures, but also changes in the tertiary structures. Under the strongly acidic condition, obvious tertiary structure changes take place after 10-ns simulation, the secondary structure elements and the loops becoming more parallel to each other, resulting in a compact state, which was stabilized by a large number of new, non-native side chain-side chain contacts. Such tertiary structure changes were not observed in the higher temperature simulation, and intuitively, they may favor the further extension of the beta-sheets and eventually the agglomeration of multiple protein molecules. The driving forces for this tertiary structure changes are discussed. Two additional 10-ns MD simulations, one with Asp202 protonated and the other with Glu196 protonated compared to the neutral pH simulation, were carried out. The results showed that the stability of the native fold is very subtle and can be strongly disturbed by eliminating a single negative charge at one of such key sites. Correlations of our results with previous experimental and theoretical studies are discussed.
PMID:_12834829 [PubMed - in process]
Acta Neuropathol (Berl). 2003 Jun 27 [Epub ahead of print]. GluR2/3, NMDAepsilon1 and GABA(A) receptors in Creutzfeldt-Jakob disease.
Ferrer I, Puig B.
Institut de Neuropatologia, Servei d'Anatomia Patologica, Hospital Universitari de Bellvitge, Carrer Feixa LLarga sn, 08907, Hospitalet de Llobregat, Spain.
The excitatory ionotropic glutamate receptors N-methyl- d-aspartate (NMDA) and alpha-amino-3-hydro-5methyl-4-isoxazole propionic acid (AMPA) receptors, and the inhibitory gamma-aminobutyric acid (GABA) receptors are major regulators of synaptic transmission in the central nervous system. Glutamate receptors AMPA GluR2/3 and NMDA R2A: NR2A (NMDAepsilon1), and GABA(A) (GABA(A) Ralpha1) receptors were examined by immunohistochemistry in the cerebral cortex (frontal cortex) entorhinal cortex, hippocampus and cerebellar cortex in nine patients with sporadic Creutzfeldt-Jakob disease (CJD) and eight age-matched controls obtained 3-8 h after death. All patients with CJD showed methionine/methionine in codon 129 of the prion protein gene. Decreased GluR2/3 immunoreactivity was found in the frontal cortex, entorhinal cortex and Purkinje cells; reduced NMDAepsilon1 immunoreactivity was found in the frontal cortex, entorhinal cortex, and molecular and granular cell layers of the cerebellum. Decreased GluR2/3 and NMDAepsilon1 immunoreactivity was also observed in the molecular layer of the dentate gyrus, but not in the hippocampus proper in cases with hippocampal involvement. GABA(A) Ralpha1 expression was markedly decreased in the granular cell layer of the cerebellum in CJD. Decreased GluR2/3 and NMDAepsilon1 expression correlated with prion protein deposition, neuron loss and spongiform degeneration in the cerebral cortex in every case. However, reduced GluR2/3 immunoreactivity in Purkinje cells was apparently independent of these parameters. In contrast to ionotropic glutamate receptors, GABA(A) Ralpha1 immunoreactivity was moderately increased in the frontal cortex, entorhinal cortex and molecular layer of the cerebellum in CJD. The present results show marked and selective abnormalities in the expression of crucial neurotransmitter receptors in CJD, ionotropic glutamate receptors being more severely affected than ionotropic GABA receptors. These findings stress selective vulnerability of glutamate receptors versus GABA receptors in CJD.
PMID:_12835949 [PubMed - as supplied by publisher]
Genes Cells. 2003 Jul;8(7):603-18. [PHI+], a novel Sup35-prion variant propagated with non-Gln/Asn oligopeptide repeats in the absence of the chaperone protein Hsp104.
Crist CG, Nakayashiki T, Kurahashi H, Nakamura Y.
Department of Basic Medical Sciences, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
BACKGROUND: The [PSI+] element of the budding yeast is an aggregated form of the translation release factor Sup35 that is propagated and transmitted cytoplasmically in a manner analogous to that of mammalian prions. The N-terminal of Sup35, necessary for [PSI+], contains oligopeptide repeats and multiple Gln/Asn residues. RESULTS: We replaced the Gln/Asn-rich prion repeats of Sup35 with non-Gln/Asn repeats from heterologous yeast strains. These non-Gln/Asn repeat Sup35s propagated a novel [PSI+] variant, [PHI+], that appeared de novo 103 times more frequent than [PSI+]. [PHI+] was stably inherited in a non-Mendelian fashion, but not eliminated upon the inactivation of Hsp104, unlike known [PSI+] elements. In vitro, non-Gln/Asn repeat domains formed amyloid fibres that were shorter and grew more slowly than did Gln/Asn-rich prion domains, while [PHI+] aggregates were smaller than [PSI+] aggregates in vivo. CONCLUSIONS: These findings suggest the existence of an alternative, Hsp104-independent pathway to replicate non-Gln/Asn variant Sup35 prion seeds.
PMID:_12839621 [PubMed - in process]
Swiss Med Wkly. 2003 May 17;133(19-20):275-82. Molecular determinants for amyloid fibril formation: lessons from lung surfactant protein C.
Johansson J.
Department of Veterinary Medical Chemistry, Swedish University of Agricultural Sciences, The Biomedical Centre, Uppsala, Sweden. jan.johanssomk.slu.se
Amyloid fibrils are polymers composed of proteins in beta-sheet conformation, which are found in at least 20 diseases for which no cure is available. These diseases include Alzheimer's disease and spongiform encephalopathies, in which the amyloid beta-peptide and the prion protein (PrP), respectively, form amyloid. All fibrils are morphologically very similar although the native structures of the corresponding proteins are widely different. Proteins that are not known to form fibrils in vivo can do so under conditions where unfolding intermediates are well populated. This indicates that fibril formation can arise from most, if not all, polypeptide chains under certain conditions, and that nature has found ways to avoid fibrillogenic protein conformations. In support of this, it was recently found that unpaired beta-strands present in native proteins are prevented from forming intermolecular beta-sheets, by strategic placement of prolines and charged residues for example. Structural studies of the lung surfactant-associated protein C (SP-C) have revealed determinants for amyloid fibril formation. The poly-valine alpha-helix of SP-C spontaneously converts to beta-sheet aggregates in vitro and SP-C amyloid fibrils are found in pulmonary alveolar proteinosis. A beta, PrP, and SP-C harbour an alpha-helix which is strongly predicted to form a beta-strand, and in all cases investigated so far such alpha-helix/beta-sheet discordance correlates with the ability to form beta-sheet aggregates and fibrils.
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