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Stanley B. Prusiner - One of the best experts on this subject based on the ideXlab platform.

  • Rapid acquisition of Beta-Sheet structure in the prion protein prior to multimer formation.
    Biological Chemistry, 1998
    Co-Authors: Karin Post, Stanley B. Prusiner, Ingrid Mehlhorn, Martin Pitschke, Oliver Schäfer, Holger Wille, Thomas R. Appel, Dieter Kirsch, Hana Serban, Detlev Riesner
    Abstract:

    The N-terminally truncated form of the prion protein, PrP 27-30, and the corresponding recombinant protein, rPrP, were solubilized in 0.2% SDS, and the transitions induced by changing the conditions from 0.2% SDS to physiological conditions, i.e. removing SDS, were characterized with respect to solubility, resistance to proteolysis, secondary structure and multimerization. Circular dichroism, electron microscopy and fluorescence correlation spectroscopy were used to study the structural transitions of PrP. Within one minute the alpha-helical structure of PrP was transformed into one that was enriched in Beta-Sheets and consisted mainly of dimers. Larger oligomers were found after 20 minutes and larger multimers exhibiting resistance to proteolysis were found after several hours. It was concluded that the monomeric alpha-helical conformation was stable in SDS or when attached to the membrane; however, the state of lowest free energy in aqueous solution at neutral pH seems to be the multimeric, Beta-Sheet enriched conformation.

  • Prion protein peptides induce alpha-helix to Beta-Sheet conformational transitions.
    Biochemistry, 1995
    Co-Authors: Jack Nguyen, Frederick Cohen, Michael A. Baldwin, Stanley B. Prusiner
    Abstract:

    The structures of synthetic peptides corresponding to regions of putative secondary structure in the cellular prion protein PrPC were studied as models for the conformational transition that features in the formation of the pathogenic isoform, PrPSc. Transgenetic studies argue that these PrP isoforms interact during the formation of PrPSc, which involves the unfolding of one or more helices of PrPC followed by refolding into Beta-Sheets. PrP residues 109-122 (H1), which were predicted to be alpha-helical, form Beta-Sheets in aqueous buffers, while the longer peptide 104-122 (104H1) and also peptide 129-141 (H2) have coil or alpha-helical structures in solution. Both 104H1 and H2 were converted into Beta-Sheets upon interaction with H1, as monitored by Fourier transform infrared (FTIR) and circular dichroism (CD) spectroscopy. The conversion was sequence-specific since mouse (Mo) H1, which differs from Syrian hamster (SHa) at two residues, was inefficient at converting SHa104H1 into the Beta-Sheet form. In buffers containing 10% acetonitrile, 104H1 was converted into the Beta-Sheet form by addition of as little as 1% H1. In addition, A Beta 11-25 and A Beta 25-35 peptides with similar physical properties to H1 were incapable of converting H2 into the Beta-Sheet form. How well these studies approximate the structural transitions in PrP that underlie the replication of prions remains to be established.

  • perturbation of the secondary structure of the scrapie prion protein under conditions that alter infectivity
    Proceedings of the National Academy of Sciences of the United States of America, 1993
    Co-Authors: Maria Gasset, Michael A. Baldwin, Robert J Fletterick, Stanley B. Prusiner
    Abstract:

    Abstract Limited proteolysis of the scrapie prion protein (PrPSc) generates PrP 27-30, which polymerizes into amyloid. By attenuated total reflection-Fourier transform infrared spectroscopy, PrP 27-30 polymers contained 54% Beta-Sheet, 25% alpha-helix, 10% turns, and 11% random coil; dispersion into detergent-lipid-protein-complexes preserved infectivity and secondary structure. Almost 60% of the Beta-Sheet was low-frequency infrared-absorbing, reflecting intermolecular aggregation. Decreased low-frequency Beta-Sheet and increased turn content were found after SDS/PAGE, which disassembled the amyloid polymers, denatured PrP 27-30, and diminished scrapie infectivity. Acid-induced transitions were reversible, whereas alkali produced an irreversible transition centered at pH 10 under conditions that diminished infectivity. Whether PrPSc synthesis involves a transition in the secondary structure of one or more domains of the cellular prion protein from alpha-helical, random coil, or turn into Beta-Sheet remains to be established.

Padmanabhan Balaram - One of the best experts on this subject based on the ideXlab platform.

  • infinite pleated Beta Sheet formed by the Beta hairpin boc Beta phe Beta phe d pro gly Beta phe Beta phe ome
    Proceedings of the National Academy of Sciences of the United States of America, 2002
    Co-Authors: Isabella L Karle, Hosahudya N. Gopi, Padmanabhan Balaram
    Abstract:

    A Beta-hairpin conformation and extended Beta-pleated Sheet assembly have been characterized by single crystal x-ray diffraction for the synthetic peptide t-butoxycarbonyl-Beta-Phe-Beta-Phe-D-Pro-Gly-b-Phe-b-Phe-methyl ester [b-Phe: (S)-b3 homophenylalanine]. The centrally located D-Pro-Gly segment nucleates a chain reversal in a type II’ Beta-turn conformation. Two intramolecular cross-strand hydrogen bonds stabilize the peptide fold. Intermolecular NH…O=C hydrogen bonds (two on each side of the hairpin) connect the hairpins into an infinitely extended Beta-Sheet. The Beta-residues cause all CAOgroups to point in the same direction, resulting in a ‘‘polar’’ Sheet by the unidirectional alignment of NH…O=C hydrogen bonds. In contrast, Beta-Sheets formed by Beta-residues have alternating directions for the hydrogen bonds, thus resulting in an ‘‘apolar’’ Sheet. The crystallographic parameters for C53H66N6O9.CH3OH are: space group P21, a = 9.854(2) A, b = 10.643(2) A, c = 25.296(4) A, Beta = 100.39(2)°, Z = 2, agreement factor R1 _ 0.065 for 3,706 data observed >4_(F) and a resolution of 0.90 A.

Hans Agren - One of the best experts on this subject based on the ideXlab platform.

  • free energy landscape for alpha helix to Beta Sheet interconversion in small amyloid forming peptide under nanoconfinement
    Journal of Physical Chemistry B, 2018
    Co-Authors: Sathish Kumar Mudedla, Arul N Murugan, Hans Agren
    Abstract:

    Understanding the mechanism of fibrillization of amyloid forming peptides could be useful for the development of therapeutics for Alzheimer's disease (AD). Taking this standpoint, we have explored in this work the free energy profile for the interconversion of monomeric and dimeric forms of amyloid forming peptides into different secondary structures namely Beta-Sheet, helix, and random coil in aqueous solution using umbrella sampling simulations and density functional theory calculations. We show that the helical structures of amyloid peptides can form β Sheet rich aggregates through random coil conformations in aqueous condition. Recent experiments ( Chem. Eur. J. 2018, 24, 3397-3402 and ACS Appl. Mater. Interfaces 2017, 9, 21116-21123) show that molybdenum disulfide nanosurface and nanoparticles can reduce the fibrillization process of amyloid Beta peptides. We have unravelled the free energy profile for the interconversion of helical forms of amyloid forming peptides into Beta-Sheet and random coil in the presence of a two-dimensional nanosurface of MoS2. Results indicate that the monomer and dimeric forms of the peptides adopt the random coil conformation in the presence of MoS2 while the helical form is preferable for the monomeric form and that the Beta-Sheet and helix forms are the preferable forms for dimers in aqueous solution. This is due to strong interaction with MoS2 and intramolecular hydrogen bonds of random coil conformation. The stabilization of random coil conformation does not lead to a β Sheet like secondary structure for the aggregate. Thus, the confinement of MoS2 promotes deaggregation of amyloid Beta peptides rather than aggregation, something that could be useful for the development of therapeutics for AD.

Eva-maria Mandelkow - One of the best experts on this subject based on the ideXlab platform.

  • tau aggregation is driven by a transition from random coil to Beta Sheet structure
    Biochimica et Biophysica Acta, 2005
    Co-Authors: Martin Von Bergen, Stefan Barghorn, Jacek Biernat, Eva-maria Mandelkow
    Abstract:

    The abnormal aggregation of the microtubule associated protein tau into paired helical filaments (PHFs) is one the hallmarks of Alzheimer's disease. The soluble protein is one of the longest natively unfolded proteins, lacking significant amounts of secondary structure over a sequence of 441 amino acids in the longest isoform. Furthermore, the unfolded character is consistent with some notable features of the protein like stability towards heat and acid treatment. It is still unclear how these characteristics support the physiological function of binding to and stabilization of microtubules. We review here some recent studies on how an unfolded protein such as tau can adopt β-structure, which then leads to the highly ordered morphology of the PHFs. The core sequence for both microtubule binding and PHF formation is the microtubule binding domain containing three or four repeats. This region alone is sufficient for PHF formation and mostly unfolded in the soluble state. A search for sequence motifs within this region crucial for PHF building revealed two hexapeptides in the second and the third repeat. Some of the genetically linked cases of FTDP-17 show missense mutations in or adjacent to these hexapeptide motifs. Proteins containing the P301L and the ΔK280 mutations exhibit accelerated aggregation. The importance of the two hexapeptides stems from their capacity to undergo a conformational change from a random coil to a Beta Sheet structure. The increase of Beta Sheet structure is a typical feature of an amyloidogenic protein and is the basis of other characteristics like a decreased sensitivity towards proteolytic degradation and Congo red binding. PHFs aggregated in vitro and in vivo contain β-Sheet structure, as judged by circular dichroism (CD) spectroscopy, Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction.

  • Tau aggregation is driven by a transition from random coil to Beta Sheet structure.
    Biochimica et biophysica acta, 2004
    Co-Authors: Martin Von Bergen, Stefan Barghorn, Jacek Biernat, Eva-maria Mandelkow
    Abstract:

    The abnormal aggregation of the microtubule associated protein tau into paired helical filaments (PHFs) is one the hallmarks of Alzheimer's disease. The soluble protein is one of the longest natively unfolded proteins, lacking significant amounts of secondary structure over a sequence of 441 amino acids in the longest isoform. Furthermore, the unfolded character is consistent with some notable features of the protein like stability towards heat and acid treatment. It is still unclear how these characteristics support the physiological function of binding to and stabilization of microtubules. We review here some recent studies on how an unfolded protein such as tau can adopt Beta-structure, which then leads to the highly ordered morphology of the PHFs. The core sequence for both microtubule binding and PHF formation is the microtubule binding domain containing three or four repeats. This region alone is sufficient for PHF formation and mostly unfolded in the soluble state. A search for sequence motifs within this region crucial for PHF building revealed two hexapeptides in the second and the third repeat. Some of the genetically linked cases of FTDP-17 show missense mutations in or adjacent to these hexapeptide motifs. Proteins containing the P301L and the DeltaK280 mutations exhibit accelerated aggregation. The importance of the two hexapeptides stems from their capacity to undergo a conformational change from a random coil to a Beta Sheet structure. The increase of Beta Sheet structure is a typical feature of an amyloidogenic protein and is the basis of other characteristics like a decreased sensitivity towards proteolytic degradation and Congo red binding. PHFs aggregated in vitro and in vivo contain Beta-Sheet structure, as judged by circular dichroism (CD) spectroscopy, Fourier transform infrared (FTIR) spectroscopy and X-ray diffraction.

Jeffery W Kelly - One of the best experts on this subject based on the ideXlab platform.

  • ww an isolated three stranded antiparallel Beta Sheet domain that unfolds and refolds reversibly evidence for a structured hydrophobic cluster in urea and gdnhcl and a disordered thermal unfolded state
    Protein Science, 2008
    Co-Authors: Edward K Koepf, Michael H Petrassi, Marius Sudol, Jeffery W Kelly
    Abstract:

    The objective of this study was to evaluate the suitability of the WW domain as a desirable model system to understand the folding and stability of an isolated three-stranded antiparallel Beta-Sheet structure. The WW domain was subjected to thermal and chaotropic denaturation/reconstitution utilizing a variety of biophysical methods. This three-stranded Sheet folds reversibly and cooperatively utilizing both urea and GdnHCl as denaturants; however, the denatured state retains structure in the form of a hydrophobic cluster involving at least one aromatic side chain. In contrast to chaotropic denaturation, thermal denaturation appears to be more complete and may be a two state process. The suitability of the WW domain for future studies aimed at understanding the kinetics and thermodynamics of antiparallel Beta-Sheet folding clearly emerges from this initial study. The most exciting and significant result in this manuscript is the finding that the chaotropic denatured state of WW has a hydrophobic cluster as discerned by near-UV CD evidence. The role that the denatured state plays in the folding and stability of a three-stranded Beta-Sheets, and its capacity for preventing aggregation may be particularly important and is the subject of ongoing studies.

  • mapping the transition state of the ww domain Beta Sheet
    Journal of Molecular Biology, 2000
    Co-Authors: Jason C Crane, Jeffery W Kelly, Edward Koepf, Martin Gruebele
    Abstract:

    The folding kinetics of a three-stranded antiparallel Beta-Sheet (WW domain) have been measured by temperature jump relaxation. Folding and activation free energies were determined as a function of temperature for both the wild-type and the mutant domain, W39F, which modifies the Beta(2)-Beta(3) hydrophobic interface. The folding rate decreases at higher temperatures as a result of the increase in the activation free energy for folding. Phi-Values were obtained for thermal perturbations allowing the primary features of the folding free energy surface to be determined. The results of this analysis indicate a significant shift from an "early" (Phi(T)=0. 4) to a "late" (Phi(T)=0.8) transition state with increasing temperature. The temperature-dependent Phi-value analysis of the wild-type WW domain and of its more stable W39F hydrophobic cluster mutant reveals little participation of residue 39 in the transition state at lower temperature. As the temperature is raised, hydrophobic interactions at the Beta(2)-Beta(3) interface gain importance in the transition state and the barrier height of the wild-type, which contains the larger tryptophan residue, increases more slowly than the barrier height of the mutant.

  • the nucleation of monomeric parallel Beta Sheet like structures and their self assembly in aqueous solution
    Bioorganic & Medicinal Chemistry, 1999
    Co-Authors: Penchit Chitnumsub, Wayne R Fiori, Hilal A Lashuel, Humberto Diaz, Jeffery W Kelly
    Abstract:

    The aromatic diacid residue 4,6-dibenzofuranbispropionic acid (1) was designed to nucleate a parallel Beta-Sheet-like structure in small peptides in aqueous solution via a hydrogen-bonded hydrophobic cluster. Even though a 14-membered ring hydrogen bond necessary for parallel Beta-Sheet formation is favored in simple amides composed of 1, this hydrogen bonding interaction does not appear to be sufficient to nucleate parallel Beta-Sheet formation in the absence of hydrophobic clustering between the dibenzofuran portion of 1 and the hydrophobic side chains of the flanking alpha-amino acids. The subsequence --hydrophobic residue-1-hydrophobic residue-- is required for folding in the context of a nucleated two-stranded parallel Beta-Sheet structure. In all cases where the peptidomimetics can fold into two diastereomeric parallel Beta-Sheet structures having different hydrogen bonding networks, these conformations appear to exchange rapidly. The majority of the parallel Beta-Sheet structures evaluated herein undergo linked intramolecular folding and self-assembly, affording a fibrillar Beta-Sheet quaternary structure. To unlink folding and assembly, asymmetric parallel Beta-Sheet structures incorporating N-methylated alpha-amino acid residues have been synthesized using a new solid phase approach. Residue 1 facilitates the folding of several peptides described within affording a monomeric parallel Beta-Sheet-like structure in aqueous solution, as ascertained by a variety of spectroscopic and biophysical methods, increasing our understanding of parallel Beta-Sheet structure.