Biochem Biophys Res Commun. 2000 Oct 5;276(3):1217-24. Copper refolding of prion protein.
Wong BS, Venien-Bryan C, Williamson RA, Burton DR, Gambetti P, Sy MS, Brown DR, Jones IM.
School of Animal and Microbial Sciences, Reading, RG6 6AH, United Kingdom.
We have shown previously that normal mouse prion protein (MoPrP) binds copper ions during protein refolding and acquires antioxidant activity. In this report, we probe the structure of the copper refolded form of MoPrP to determine how copper binding alters the secondary and tertiary features of the protein. Circular dichroism showed that recombinant MoPrP prepared in the presence of copper (as Cu(++)) showed an increased signal in the 210-220 nm range of the spectrum. Changes in protein conformation were localised to the N-terminal region of MoPrP using a panel of antibodies to assess epitope accessibility. The copper refolded recombinant prion protein had reduced proteinase K (PK) sensitivity when compared to the non-copper liganded form. Reduced PK sensitivity was not due to aggregation however as high resolution electron microscopy showed a homogenous preparation with little aggregate when compared to the non-copper form. Finally, disruption of the single disulphide linkage in MoPrP significantly diminished the antioxidant activity of the copper refolded form suggesting that activity was not solely dependent on bound copper but also on a conformation enabled by the formation of the disulphide bond. 2000 Academic Press.
PMID:_11027613
Nature. 2000 Sep 28;407(6803):477-83. A yeast prion provides a mechanism for genetic variation and phenotypic diversity.
True HL, Lindquist SL.
Department of Molecular Genetics and Cell Biology, Howard Hughes Medical Institute, The University of Chicago, Illinois 60637, USA.
A major enigma in evolutionary biology is that new forms or functions often require the concerted effects of several independent genetic changes. It is unclear how such changes might accumulate when they are likely to be deleterious individually and be lost by selective pressure. The Saccharomyces cerevisiae prion [PSI+] is an epigenetic modifier of the fidelity of translation termination, but its impact on yeast biology has been unclear. Here we show that [PSI+] provides the means to uncover hidden genetic variation and produce new heritable phenotypes. Moreover, in each of the seven genetic backgrounds tested, the constellation of phenotypes produced was unique. We propose that the epigenetic and metastable nature of [PSI+] inheritance allows yeast cells to exploit pre-existing genetic variation to thrive in fluctuating environments. Further, the capacity of [PSI+] to convert previously neutral genetic variation to a non-neutral state may facilitate the evolution of new traits.
PMID:_11028992
Arch Neurol. 2002 Nov;59(11):1815-8. Serial positron emission tomographic findings in an atypical presentation of fatal familial insomnia.
Bar KJ, Hager F, Nenadic I, Opfermann T, Brodhun M, Tauber RF, Patt S, Schulz-Schaeffer W, Gottschild D, Sauer H.
Department of Psychiatry, Friedrich-Schiller-Universitat of Jena, Germany. Karl-Juergen.Baeed.uni-jena.de
BACKGROUND: Genetic analyses of fatal familial insomnia, a prion disease, disclose a broader range of symptoms than previously described. Although insomnia and dysautonomia have been described as hallmarks of the disease, there is substantial variability in clinical presentation. OBJECTIVE: To evaluate serial fluorodeoxyglucose positron emission tomographic and electroencephalographic findings in atypical fatal familial insomnia without clinical insomnia. PATIENT: A 63-year-old man who had a history of gait ataxia developed rapidly progressive dementia with mild dysautonomic features. Genetic investigation confirmed diagnosis of fatal familial insomnia (D178N mutation of the prion protein gene and Val/Met polymorphism on position 129 of the mutated allele) with typical neuropathologic findings. RESULTS: Clinical signs were not specific. An electroencephalogram showed scanty triphasiclike elements and general slowing. We found thalamic hypometabolism in positron emission tomographic scans to be present in a very early stage with progressive deterioration, and patchy cortical alterations showing progression over 6 months. CONCLUSIONS: In the absence of clear clinical signs, an electroencephalogram was of major diagnostic value, although its specificity in fatal familial insomnia is under debate. Selective thalamic hypometabolism seems to be an early marker in fatal familial insomnia, while cortical changes vary with clinical presentation and stage.
PMID:_12433271
Glycobiology. 2000 Oct;10(10):959-74. Molecular dynamics simulation of human prion protein including both N-linked oligosaccharides and the GPI anchor.
Zuegg J, Gready JE.
Division of Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, P.O. Box 334, Canberra, ACT 2601, Australia.
Although glycosylation appears to protect prion protein (PrP(C)) from the conformational transition to the disease-associated scrapie form (PrP(Sc)), available NMR structures are for non-glycosylated PrP(C), only. To investigate the influence of both the two N-linked glycans, Asn181 and Asn197, and of the GPI anchor attached to Ser230, on the structural, dynamical and electrostatic behavior of PrP, we have undertaken molecular dynamics simulations on the C-terminal region of human prion protein HU:PrP(90-230), with and without the three glycans. The simulations used the AMBER94 force field in a periodic box model with explicit water molecules, considering all long-range electrostatic interactions. The results suggest the structured part of the protein, HU:PrP(127-227) is stabilized overall from addition of the glycans, specifically by extensions of Helix-B and Helix-C and reduced flexibility of the linking turn containing Asn197, although some regions such as residues in the turn (165-170) between Strand-B and Helix-B have increased flexibility. The stabilization appears indirect, by reducing the mobility of the surrounding water molecules, and not from specific interactions such as H bonds or ion pairs. The results are consistent with glycosylation at Asn197 having a stabilizing role, while that at Asn181, in a region with already stable secondary structure, having a more functional role, in agreement with literature suggestions. Due to three negatively charged SiaLe(x) groups per N-glycan, the surface electrostatic properties change to a negative electrostatic field covering most of the C-terminal part, including the surface of Helix-B and Helix-C, while the positively charged N-terminal part PrP(90-126) of undefined structure creates a positive potential. The unusual hydrophilic Helix-A (144-152) is not covered by either of these dominant electrostatic fields, and modeling shows it could readily dimerize in anti parallel fashion. In combination with separate simulations of the GPI anchor in a membrane model, the results show the GPI anchor is highly flexible and would maintain the protein at a distance between 9 and 13 A from the membrane surface, with little influence on its structure or orientational freedom.
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