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Berlin Brandenburg

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  • 1
    Language: English
    In: Journal of the American Chemical Society, 26 August 2015, Vol.137(33), pp.10554-62
    Description: An ability to design peptide-based nanotubes (PNTs) rationally with defined and mutable internal channels would advance understanding of peptide self-assembly, and present new biomaterials for nanotechnology and medicine. PNTs have been made from Fmoc dipeptides, cyclic peptides, and lock-washer helical bundles. Here we show that blunt-ended α-helical barrels, that is, preassembled bundles of α-helices with central channels, can be used as building blocks for PNTs. This approach is general and systematic, and uses a set of de novo helical bundles as standards. One of these bundles, a hexameric α-helical barrel, assembles into highly ordered PNTs, for which we have determined a structure by combining cryo-transmission electron microscopy, X-ray fiber diffraction, and model building. The structure reveals that the overall symmetry of the peptide module plays a critical role in ripening and ordering of the supramolecular assembly. PNTs based on pentameric, hexameric, and heptameric α-helical barrels sequester hydrophobic dye within their lumens.
    Keywords: Nanotechnology -- Methods ; Nanotubes, Peptide -- Chemistry
    ISSN: 00027863
    E-ISSN: 1520-5126
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  • 2
    Language: English
    In: Journal of the American Chemical Society, 16 October 2013, Vol.135(41), pp.15565-78
    Description: Design of a structurally defined helical assembly is described that involves recoding of the amino acid sequence of peptide GCN4-pAA. In solution and the crystalline state, GCN4-pAA adopts a 7-helix bundle structure that resembles a supramolecular lock washer. Structurally informed mutagenesis of the sequence of GCN4-pAA afforded peptide 7HSAP1, which undergoes self-association into a nanotube via noncovalent interactions between complementary interfaces of the coiled-coil lock-washer structures. Biophysical measurements conducted in solution and the solid state over multiple length scales of structural hierarchy are consistent with self-assembly of nanotube structures derived from 7-helix bundle subunits. The dimensions of the supramolecular assemblies are similar to those observed in the crystal structure of GCN4-pAA. Fluorescence studies of the interaction of 7HSAP1 with the solvatochromic fluorophore PRODAN indicated that the nanotubes could encapsulate shape-appropriate small molecules with high binding affinity.
    Keywords: Nanotubes -- Chemistry ; Peptides -- Chemistry
    ISSN: 00027863
    E-ISSN: 1520-5126
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  • 3
    Language: English
    In: Biochemistry, 01 November 2011, Vol.50(43), pp.9184-91
    Description: For nearly four decades, the formation of amyloid fibrils by the inflammation-related protein serum amyloid A (SAA) has been pathologically linked to the disease amyloid A (AA) amyloidosis. However, here we show that the nonpathogenic murine SAA2.2 spontaneously forms marginally stable amyloid fibrils at 37 °C that exhibit cross-beta structure, binding to thioflavin T, and fibrillation by a nucleation-dependent seeding mechanism. In contrast to the high stability of most known amyloid fibrils to thermal and chemical denaturation, experiments monitored by glutaraldehyde cross-linking/SDS-PAGE, thioflavin T fluorescence, and light scattering (OD(600)) showed that the mature amyloid fibrils of SAA2.2 dissociate upon incubation in 〉1.0 M urea or 〉45 °C. When considering the nonpathogenic nature of SAA2.2 and its ~1000-fold increased concentration in plasma during an inflammatory response, its extreme in vitro amyloidogenicity under physiological-like conditions suggest that SAA amyloid might play a functional role during inflammation. Of general significance, the combination of methods used here is convenient for exploring the stability of amyloid fibrils that are sensitive to urea and temperature. Furthermore, our studies imply that analogous to globular proteins, which can possess structures ranging from intrinsically disordered to extremely stable, amyloid fibrils formed in vivo might have a broader range of stabilities than previously appreciated with profound functional and pathological implications.
    Keywords: Amyloid -- Metabolism ; Serum Amyloid A Protein -- Metabolism
    ISSN: 00062960
    E-ISSN: 1520-4995
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  • 4
    Language: English
    In: Biochemistry, 29 March 2011, Vol.50(12), pp.2061-71
    Description: Amyloid-like fibrous crystals formed by the peptide KFFEAAAKKFFE have been previously characterized and provide an ideal model system to examine the importance of specific interactions by introducing specific substitutions. We find that the removal of any phenylalanine residue completely abrogates assembly ability, while charged residues modulate interactions within the structure resulting in alternative fibrillar morphologies. X-ray fiber diffraction analysis reveals that the essential backbone packing of the peptide molecules is maintained, while small changes accommodate differences in side chain size in the variants. We conclude that even very short peptides are adaptable and add to the growing knowledge regarding amyloid polymorphisms. Additionally, this work impacts on our understanding of the importance of residue composition for amyloidogenic peptides, in particular the roles of electrostatic, aromatic, and hydrophobic interactions in amyloid assembly.
    Keywords: Hydrophobic and Hydrophilic Interactions ; Protein Multimerization ; Static Electricity ; Amyloid Beta-Peptides -- Chemistry
    ISSN: 00062960
    E-ISSN: 1520-4995
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  • 5
    In: Chemical Communications, 2011, Vol.47(44), pp.12071-12073
    Description: Addition of divalent cations to a solution of a naphthalene-diphenylalanine that forms worm-like micelles at high pH results in the formation of a rigid, self-supporting hydrogel.
    Keywords: Dipeptides -- Chemistry ; Hydrogels -- Chemistry ; Naphthalenes -- Chemistry ; Phenylalanine -- Analogs & Derivatives;
    ISSN: 1359-7345
    E-ISSN: 1364-548X
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  • 6
    Language: English
    In: Journal of the American Chemical Society, 28 June 2017, Vol.139(25), pp.8685-8692
    Description: We report a peptide-based multichromophoric hydrogelator system, wherein π-electron units with different inherent spectral energies are spatially controlled within peptidic 1-D nanostructures to create localized energy gradients in aqueous environments. This is accomplished by mixing different π-conjugated peptides prior to initiating self-assembly through solution acidification. We can vary the kinetics of the assembly and the degree of self-sorting through the choice of the assembly trigger, which changes the kinetics of acidification. The hydrolysis of glucono-δ-lactone (GdL) provides a slow pH drop that allows for stepwise triggering of peptide components into essentially self-sorted nanostructures based on subtle pK differences, whereas HCl addition leads to a rapid formation of mixed components within a nanostructure. Using H NMR spectroscopy and fiber X-ray diffraction, we determine the conditions and peptide mixtures that favor self-sorting or intimate comixing. Photophysical investigations in the solution phase provide insight into the correlation of energy-transport processes occurring within the assemblies to the structural organization of the π-systems.
    Keywords: Hydrogels -- Chemistry ; Peptides -- Chemistry
    ISSN: 00027863
    E-ISSN: 1520-5126
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  • 7
    Language: English
    In: BBA - Proteins and Proteomics, March 2016, Vol.1864(3), pp.249-259
    Description: Oligomeric assemblies are postulated to be proximate neurotoxic species in human diseases associated with aberrant protein aggregation. Their heterogeneous and transient nature makes their structural characterization difficult. Size distributions of oligomers of several amyloidogenic proteins, including amyloid β-protein (Aβ) relevant to Alzheimer's disease (AD), have been previously characterized in vitro by photo-induced cross-linking of unmodified proteins (PICUP) followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Due to non-physiological conditions associated with the PICUP chemistry, Aβ oligomers cross-linked by PICUP may not be representative of in vivo conditions. Here, we examine an alternative Copper and Hydrogen peroxide Induced Cross-linking of Unmodified Proteins (CHICUP), which utilizes naturally occurring divalent copper ions and hydrogen peroxide and does not require photo activation. Our results demonstrate that CHICUP and PICUP applied to the two predominant Aβ alloforms, Aβ40 and Aβ42, result in similar oligomer size distributions. Thioflavin T fluorescence data and atomic force microscopy images demonstrate that both CHICUP and PICUP stabilize Aβ oligomers and attenuate fibril formation. Relative to noncross-linked peptides, CHICUP-treated Aβ40 and Aβ42 cause prolonged disruption to biomimetic lipid vesicles. CHICUP-stabilized Aβ oligomers link the amyloid cascade, metal, and oxidative stress hypotheses of AD into a more comprehensive understanding of the molecular basis of AD pathology. Because copper and hydrogen peroxide are elevated in the AD brain, CHICUP-stabilized Aβ oligomers are biologically relevant and should be further explored as a new therapeutic target.
    Keywords: Amyloid Fibril ; Alzheimer'S Disease ; Amyloid Β-Protein ; Oligomer ; Copper ; Hydrogen Peroxide ; Chemistry ; Anatomy & Physiology
    ISSN: 1570-9639
    E-ISSN: 1878-1454
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  • 8
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 28 January 2014, Vol.111(4), pp.1539-44
    Description: The Ser52Pro variant of transthyretin (TTR) produces aggressive, highly penetrant, autosomal-dominant systemic amyloidosis in persons heterozygous for the causative mutation. Together with a minor quantity of full-length wild-type and variant TTR, the main component of the ex vivo fibrils was the residue 49-127 fragment of the TTR variant, the portion of the TTR sequence that previously has been reported to be the principal constituent of type A, cardiac amyloid fibrils formed from wild-type TTR and other TTR variants [Bergstrom J, et al. (2005) J Pathol 206(2):224-232]. This specific truncation of Ser52Pro TTR was generated readily in vitro by limited proteolysis. In physiological conditions and under agitation the residue 49-127 proteolytic fragment rapidly and completely self-aggregates into typical amyloid fibrils. The remarkable susceptibility to such cleavage is likely caused by localized destabilization of the β-turn linking strands C and D caused by loss of the wild-type hydrogen-bonding network between the side chains of residues Ser52, Glu54, Ser50, and a water molecule, as revealed by the high-resolution crystallographic structure of Ser52Pro TTR. We thus provide a structural basis for the recently hypothesized, crucial pathogenic role of proteolytic cleavage in TTR amyloid fibrillogenesis. Binding of the natural ligands thyroxine or retinol-binding protein (RBP) by Ser52Pro variant TTR stabilizes the native tetrameric assembly, but neither protected the variant from proteolysis. However, binding of RBP, but not thyroxine, inhibited subsequent fibrillogenesis.
    Keywords: Misfolding ; Protein Aggregation ; Amyloid -- Metabolism ; Prealbumin -- Metabolism ; Proline -- Metabolism ; Serine -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 9
    Language: English
    In: FEBS Letters, 24 October 2015, Vol.589(21), pp.3228-3236
    Description: Soluble Amyloid-beta (Aβ) oligomers are a source of cytotoxicity in Alzheimer’s disease (AD). The toxicity of Aβ oligomers may arise from their ability to interact with and disrupt cellular membranes mediated by GM1 ganglioside receptors within these membranes. Therefore, inhibition of Aβ–membrane interactions could provide a means of preventing the toxicity associated with Aβ. Here, using Surface Plasmon field-enhanced Fluorescence Spectroscopy, we determine that the lanthanide, Europium III chloride (Eu ), strongly binds to GM1 ganglioside-containing membranes and prevents the interaction with Aβ42 leading to a loss of the peptides ability to cause membrane permeation. Here we discuss the molecular mechanism by which Eu inhibits Aβ42-membrane interactions and this may lead to protection of membrane integrity against Aβ42 induced toxicity.
    Keywords: Amyloid-Β Peptide ; Europium ; Gm1 Ganglioside ; Permeation Inhibition ; Alzheimer’s Disease ; Protein Misfolding ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0014-5793
    E-ISSN: 1873-3468
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  • 10
    Language: English
    In: Journal of Molecular Biology, 30 January 2015, Vol.427(2), pp.550-562
    Description: Protein and peptide self-assembly is a powerful design principle for engineering of new biomolecules. More sophisticated biomaterials could be built if both the structure of the overall assembly and that of the self-assembling building block could be controlled. To approach this problem, we developed a computational design protocol to enable design of self-assembling peptides with predefined structure. The protocol was used to design a peptide building block with a βαβ fold that self-assembles into fibrillar structures. The peptide associates into a double β-sheet structure with tightly packed α-helices decorating the exterior of the fibrils. Using circular dichroism, Fourier transform infrared spectroscopy, electron microscopy and X-ray fiber diffraction, we demonstrate that the peptide adopts the designed conformation. The results demonstrate that computational protein design can be used to engineer protein and peptide assemblies with predefined three-dimensional structures, which can serve as scaffolds for the development of functional biomaterials. Rationally designed proteins and peptides could also be used to investigate the subtle energetic and entropic tradeoffs in natural self-assembly processes and the relation between assembly structure and assembly mechanism. We demonstrate that the designed peptide self-assembles with a mechanism that is more complicated than expected, in a process where small changes in solution conditions can lead to significant differences in assembly properties and conformation. These results highlight that formation of structured protein/peptide assemblies is often dependent on the formation of weak but highly precise intermolecular interactions.
    Keywords: Self-Assembly ; Computational Protein Design ; Protein Structure ; Fourier Transform Infrared Spectroscopy ; de Novo Design ; Biology ; Chemistry
    ISSN: 0022-2836
    E-ISSN: 1089-8638
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