J Am Soc Mass Spectrom. 2002 Sep;13(9):1065-77. Precursor ion scanning for detection and structural characterization of heterogeneous glycopeptide mixtures.
Ritchie MA, Gill AC, Deery MJ, Lilley K.
Institute for Animal Health, Compton, Berkshire, United Kingdom.
The structure of N-linked glycans is determined by a complex, anabolic, intracellular pathway but the exact role of individual glycans is not always clear. Characterization of carbohydrates attached to glycoproteins is essential to aid understanding of this complex area of biology. Specific mass spectral detection of glycopeptides from protein digests may be achieved by on-line HPLC-MS, with selected ion monitoring (SIM) for diagnostic product ions generated by cone voltage fragmentation, or by precursor ion scanning for terminal saccharide product ions, which can yield the same information more rapidly. When glycosylation is heterogeneous, however, these approaches can result in spectra that are complex and poorly resolved. We have developed methodology, based around precursor ion scanning for ions of high m/z, that allows site specific detection and structural characterization of glycans at high sensitivity and resolution. These methods have been developed using the standard glycoprotein, fetuin, and subsequently applied to the analysis of the N-linked glycans attached to the scrapie-associated prion protein, PrP(Sc). These glycans are highly heterogeneous and over 30 structures have been identified and characterized site specifically. Product ion spectra have been obtained on many glycopeptides confirming structure assignments. The glycans are highly fucosylated and carry Lewis X or sialyl Lewis X epitopes and the structures are in-line with previous results.
PMID:_12322954
Chembiochem. 2002 Jul 2;3(7):637-42. Amyloid architecture: complementary assembly of heterogeneous combinations of three or four peptides into amyloid fibrils.
Takahashi Y, Ueno A, Mihara H.
Department of Bioengineering Graduate School of Bioscience and Biotechnology Tokyo Institute of Technology, Yokohama 226-8501, Japan.
The amyloid fibril is a misfolded and undesirable state for proteins that has been proposed to be a causative agent for a variety of fatal diseases known as amyloid diseases, such as Alzheimer's and prion diseases. However, the fibril has a highly ordered tertiary structure in which numerous beta-strand polypeptide chains align in a regular pattern. Thus, this kind of fibril has the potential to be engineered into proteinaceous materials. Amyloid fibrils of misfolded proteins primarily comprise a single polypeptide species, that is, the self-assembly is homogeneous. We here found that three or four designed peptides can assemble heterogeneously and cooperatively into amyloid fibrils, a process accompanied by a drastic secondary structural transition from alpha helix to beta sheet. Heterogeneous assembly into fibrils is accomplished by complementary electrostatic interactions between three or four peptide species, each of which is not able to self-assemble homogeneously. These findings will lead to a novel way to study the molecular details of amyloid formation and also to design beta-sheet peptidyl materials.
PMID:_12324997
Ann Neurol. 2002 Oct;52(4):416-20. Valproic acid treatment results in increased accumulation of prion proteins.
Shaked GM, Engelstein R, Avraham I, Rosenmann H, Gabizon R.
Department of Neurology, Agnes Ginges Center for Human Neurogenetics, Hadassah University Hospital, Jerusalem, Israel.
PrP(Sc), the only identified component of the prion, is an aberrant isoform of PrP(C), a glycoprotein of unknown function. In this study, it was shown that valproic acid, a widely used antiepileptic drug, can cause an increase of several orders of magnitude in the accumulation of PrP(C) in normal neuroblastoma cells (N2a), and of both PrP isoforms in scrapie infected neuroblastoma cells (ScN2a). Although preliminary results indicate that valproic acid administration to hamsters inoculated with prions had no significant effect on disease incubation time, it is suggested that administration of valproic acid to humans at risk of developing Creutzfeldt-Jakob disease should be evaluated with caution.
PMID:_12325069
Ann Neurol. 2002 Oct;52(4):503-6. Quinacrine does not prolong survival in a murine Creutzfeldt-Jakob disease model.
Collins SJ, Lewis V, Brazier M, Hill AF, Fletcher A, Masters CL.
Department of Pathology, University of Melbourne, Parkville, Victoria, Australia. stevenjnimelb.edu.au
Paramount among issues relating to the transmissible spongiform encephalopathies (also known as prion diseases) is the absence of any effective therapy. This need has been heightened by the substantial European and emerging global problem of bovine spongiform encephalopathy and consequent variant Creutzfeldt-Jakob disease. Stimulated by the recent reports of a potent antiprion effect in cell culture-based clearance assays, we studied the utility of quinacrine in a well-characterized in vivo model of mouse-adapted transmissible spongiform encephalopathy. Our results failed to show any evidence that quinacrine is effective when using the simple but objective measure of survival prolongation.
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