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Selected AbstractsOligopeptide-mediated acceleration of amyloid fibril formation of amyloid ,(A,) and ,-synuclein fragment peptide (NAC)JOURNAL OF PEPTIDE SCIENCE, Issue 1 2004Dr Yoshihiro Kuroda Abstract The effects of oligopeptides on the secondary structures of A, and NAC, a fragment of ,-synuclein protein, were studied by circular dichroism (CD) spectra. The effects of oligopeptides on the amyloid fibril formation were also studied by fluorescence spectra due to thioflavine-T. The oligopeptides were composed of a fragment of A, or NAC and were interposed by acidic or basic amino acid residues. The peptide, Ac-ELVFFAKK-NH2, which involved a fragment Leu-Val-Phe-Phe-Ala at A,(17,21), had no effect on the secondary structures of A,(1,28) in 60% or 90% trifluoroethanol (TFE) solutions at both pH 3.2 and pH 7.2. However, it showed pronounced effects on the secondary structure of A,(1,28) at pH 5.4. The Ac-ELVFFAKK-NH2 reduced the ,-helical content, while it increased the ,-sheet content of A,(1,28). In phosphate buffer solutions at pH 7.0, Ac-ELVFFAKK-NH2 had little effect on the secondary structures of A,(1,28). However, it accelerated amyloid fibril formation when monitored by fluorescence spectra due to thioflavine-T. On the other hand, LPFFD, a peptide known as a ,-sheet breaker, caused neither an appreciable extent of change in the secondary structure nor amyloid fibril formation in the same buffer solution. The peptide, Ac-ETVK-NH2, which involved a fragment Thr-Val at NAC(21,22), had no effect on the secondary structure of NAC in 90% TFE and in isotonic phosphate buffer. However, Ac-ETVK-NH2 in water with small amounts of NaN3 and hexafluoroisopropanol greatly increased the ,-sheet content of NAC after standing the solution for more than 1 week. Interestingly, in this solution, Ac-ETVK-NH2, accelerated the fibril formation of NAC. It was concluded that an oligopeptide that involves a fragment of amyloidogenic proteins could be a trigger for the formation of amyloid plaques of the proteins even when it had little effect on the secondary structures of the proteins as monitored by CD spectra for a short incubation time. Copyright © 2003 European Peptide Society and John Wiley & Sons, Ltd. [source] Vaccination as a Therapeutic Approach to Alzheimer's DiseaseMOUNT SINAI JOURNAL OF MEDICINE: A JOURNAL OF PERSONALIZED AND TRANSLATIONAL MEDICINE, Issue 1 2010Thomas Wisniewski MD Abstract Alzheimer's disease is the most common cause of dementia worldwide. Alzheimer's disease is a member of a broad range of neurodegenerative diseases characterized pathologically by the conformational change of a normal protein into a pathological conformer with a high ,-sheet content that renders it neurotoxic. In the case of Alzheimer's disease, the normal soluble amyloid , peptide is converted into oligomeric/fibrillar amyloid ,. The oligomeric forms of amyloid , have been hypothesized to be the most toxic, whereas fibrillar amyloid , becomes deposited as amyloid plaques and congophilic angiopathy, which both serve as neuropathological markers of the disease. In addition, the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is a critical part of the pathology. Numerous therapeutic interventions are under investigation to prevent and treat Alzheimer's disease. Among the most exciting and advanced of these approaches is vaccination. Immunomodulation is being tried for a range of neurodegenerative disorders, with great success being reported in most model animal trials; however, the much more limited human data have shown more modest clinical success so far, with encephalitis occurring in a minority of patients treated with active immunization. The immunomodulatory approaches for neurodegenerative diseases involve targeting a self-protein, albeit in an abnormal conformation; hence, effective enhanced clearance of the disease-associated conformer has to be balanced with the potential risk of stimulating excessive toxic inflammation within the central nervous system. The design of future immunomodulatory approaches that are more focused is dependent on addressing a number of questions, including when is the best time to start immunization, what are the most appropriate targets for vaccination, and is amyloid central to the pathogenesis of Alzheimer's disease or is it critical to target tau-related pathology also. In this review, we discuss the past experience with vaccination for Alzheimer's disease and the development of possible future strategies that target both amyloid ,,related and tau-related pathologies. Mt Sinai J Med 77:17&–31, 2010. © 2010 Mount Sinai School of Medicine [source] Structural composition of ,I - and ,II -proteinsPROTEIN SCIENCE, Issue 2 2003Narasimha Sreerama Abstract Circular dichroism spectra of proteins are sensitive to protein secondary structure. The CD spectra of ,-rich proteins are similar to those of model ,-helices, but ,-rich proteins exhibit CD spectra that are reminiscent of CD spectra of either model ,-sheets or unordered polypeptides. The existence of these two types of CD spectra for ,-rich proteins form the basis for their classification as ,I - and ,II -proteins. Although the conformation of ,-sheets is largely responsible for the CD spectra of ,I -proteins, the source of ,II -protein CD, which resembles that of unordered polypeptides, is not completely understood. The CD spectra of unordered polypeptides are similar to that of the poly(Pro)II helix, and the poly(Pro)II-type (P2) structure forms a significant fraction of the unordered conformation in globular proteins. We have compared the ,-sheet and P2 structure contents in ,-rich proteins to understand the origin of ,II -protein CD. We find that ,II -proteins have a ratio of P2 to ,-sheet content greater than 0.4, whereas for ,I -proteins this ratio is less than 0.4. The ,-sheet content in ,I -proteins is generally higher than that in ,II -proteins. The origin of two classes of CD spectra for ,-rich proteins appears to lie in their relative ,-sheet and P2 structure contents. [source] The prion domain of yeast Ure2P induces autocatalytic formation of amyloid fibers by a recombinant fusion proteinPROTEIN SCIENCE, Issue 3 2000Martin Schlumpberger Abstract The Ure2 protein from Saccharomyces cerevisiae has been proposed to undergo a prion-like autocatalytic conformational change, which leads to inactivation of the protein, thereby generating the [URE3] phenotype. The first 65 amino acids, which are dispensable for the cellular function of Ure2p in nitrogen metabolism, are necessary and sufficient for [URE3] (Masison & Wickner, 1995), leading to designation of this domain as the Ure2 prion domain (UPD). We expressed both UPD and Ure2 as glutathione- S -transferase (GST) fusion proteins in Escherichia coli and observed both to be initially soluble. Upon cleavage of GST-UPD by thrombin, the released UPD formed ordered fibrils that displayed amyloid-like characteristics, such as Congo red dye binding and green-gold birefringence. The fibrils exhibited high ,-sheet content by Fourier transform infrared spectroscopy. Fiber formation proceeded in an autocatalytic manner. In contrast, the released, full-length Ure2p formed mostly amorphous aggregates; a small amount polymerized into fibrils of uniform size and morphology. Aggregation of Ure2p could be seeded by UPD fibrils. Our results provide biochemical support for the proposal that the [URE3] state is caused by a self-propagating inactive form of Ure2p. We also found that the uncleaved GST-UPD fusion protein could polymerize into amyloid fibrils by a strictly autocatalytic mechanism, forcing the GST moiety of the protein to adopt a new, ,-sheet-rich conformation. The findings on the GST-UPD fusion protein indicate that the ability of the prion domain to mediate a prion-like conversion process is not specific for or limited to the Ure2p. [source] Spontaneous conformational change within the prion protein,implications for disease pathogenesis?BIOESSAYS, Issue 9 2001Graham S. Jackson A recent paper by Leclerc et al(1) describes how recombinant hamster prion protein can undergo a spontaneous change in conformation to a structure that has features in common with PrPSc. Structural change in the host prion protein, PrPC to an insoluble and aggregated form with increased ,-sheet content (PrPSc) is central to the pathology of prion diseases.(2) A detailed understanding of the nature of these conformational changes will increase our knowledge of the molecular basis of prion pathology. These findings may have implications for how the disease is initiated and provide a format for further investigation. BioEssays 23:772,774, 2001. © 2001 John Wiley & Sons, Inc. [source] Conformational transition and liquid crystalline state of regenerated silk fibroin in waterBIOPOLYMERS, Issue 6 2008Xin-Gui Li Abstract The conformational transition of molecular chains of regenerated silk fibroin (SF) aqueous solution is systematically investigated by circular dichroism, Raman, IR, and UV,vis spectroscopies. It is found that an initial random coil conformation of the SF can be readily changed into an ordered ,-sheet structure by optimizing the solution conditions, such as the SF concentration, pH, temperature, or metal-ion content. Circular dichroic spectra quantitatively confirm a steadily decreased content of the random coil conformation but a significantly increased ,-sheet content after an ultrasonic or extruding treatment. Furthermore, the extrusion is more powerful to achieve high ,-sheet content than the ultrasonic. It is interesting that the polarized optical micrographs of the SF aqueous solution extruded by injection illustrate the formation and existence of liquid crystalline state. A study of extrusion in vitro could be used as a model system to understand the natural silk spinning process in silkworm. © 2007 Wiley Periodicals, Inc. Biopolymers 89: 497,505, 2008. This article was originally published online as an accepted preprint. The "Published Online" date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com [source] Vibrational infrared conformational studies of model peptides representing the semicrystalline domains of Bombyx mori silk fibroin,BIOPOLYMERS, Issue 5 2005Paola Taddei Abstract The structural organization of Bombyx mori silk fibroin was investigated by infrared (IR) spectroscopy. To this aim, (AG)15 and other model peptides of varying chain length, containing tyrosine (Y), valine (V), and serine (S) in the basic (AG)n sequence were synthesized by the solid phase method and their spectroscopic properties were determined. Both the position and the relative content of Y, V, and S residues in the (AG)n model system appeared critical in determining the preferred conformation, i.e., silk I, silk II, and unordered structures. Curve fitting analysis in the amide I range showed that the model peptides with prevailing silk II structure displayed different ,-sheet content, which was dependent on the degree of interruption of the (AG)n sequence. In this regard, the bands at about 1000 and 980 cm,1, specifically assigned to the AG sequence of the B. mori silk fibroin chain, were identified as marker of the degree of interruption of the (AG)n sequence. A stable silk I structure was observed only when the Y residue was located near the chain terminus, while a silk I , silk II conformational transition occurred when it was positioned in the central region of the peptide. Analysis of the second-derivative spectra in the amide I range allowed us to identify a band at 1639 cm,1 (4 , 1 hydrogen-bonded type II ,-turns), which is characteristic of the silk I conformation. © 2005 Wiley Periodicals, Inc. Biopolymers 78: 249,258, 2005 [source] | ||||||||||