Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

X-ray Crystallographic Structure of a Compact Dodecamer from a Peptide Derived from A?16-36.

ABSTRACT: The assembly of the ?-amyloid peptide, A?, into soluble oligomers is associated with neurodegeneration in Alzheimer's disease. The A? oligomers are thought to be composed of ?-hairpins. Here, the effect of shifting the residue pairing of the ?-hairpins on the structures of the oligomers that form is explored through X-ray crystallography. Three residue pairings were investigated using constrained macrocyclic ?-hairpins in which A?30-36 is juxtaposed with A?17-23, A?16-22, and A?15-21. The A?16-22-A?30-36 pairing forms a compact ball-shaped dodecamer composed of fused triangular trimers. This dodecamer may help explain the structures of the trimers and dodecamers formed by full-length A?.

SUBMITTER: Salveson PJ

PROVIDER: S-EPMC5776032 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

X-ray Crystallographic Structure of a Compact Dodecamer from a Peptide Derived from Aβ16-36.

Salveson Patrick J PJ Spencer Ryan K RK Kreutzer Adam G AG Nowick James S JS

Organic letters 20170615 13

The assembly of the β-amyloid peptide, Aβ, into soluble oligomers is associated with neurodegeneration in Alzheimer's disease. The Aβ oligomers are thought to be composed of β-hairpins. Here, the effect of shifting the residue pairing of the β-hairpins on the structures of the oligomers that form is explored through X-ray crystallography. Three residue pairings were investigated using constrained macrocyclic β-hairpins in which Aβ30-36 is juxtaposed with Aβ17-23, Aβ16- ...[more]

PMID: 28683555

Similar Datasets

Interpenetrating Cubes in the X-ray Crystallographic Structure of a Peptide Derived from Medin19-36.

Project description:Amyloidogenic peptides and proteins are rich sources of supramolecular assemblies. Sequences derived from well-known amyloids, including Aβ, human islet amyloid polypeptide, and tau have been found to assemble as fibrils, nanosheets, ribbons, and nanotubes. The supramolecular assembly of medin, a 50-amino acid peptide that forms fibrillary deposits in aging human vasculature, has not been heavily investigated. In this work, we present an X-ray crystallographic structure of a cyclic β-sheet peptide derived from the 19-36 region of medin that assembles to form interpenetrating cubes. The edge of each cube is composed of a single peptide, and each vertex is occupied by a divalent metal ion. This structure may be considered a metal-organic framework (MOF) containing a large peptide ligand. This work demonstrates that peptides containing Glu or Asp that are preorganized to adopt β-hairpin structures can serve as ligands and assemble with metal ions to form MOFs.

| S-EPMC7819122 | biostudies-literature

X-ray Crystallographic Structures of a Trimer, Dodecamer, and Annular Pore Formed by an A?17-36 ?-Hairpin.

Project description:High-resolution structures of oligomers formed by the ?-amyloid peptide A? are needed to understand the molecular basis of Alzheimer's disease and develop therapies. This paper presents the X-ray crystallographic structures of oligomers formed by a 20-residue peptide segment derived from A?. The development of a peptide in which A?17-36 is stabilized as a ?-hairpin is described, and the X-ray crystallographic structures of oligomers it forms are reported. Two covalent constraints act in tandem to stabilize the A?17-36 peptide in a hairpin conformation: a ?-linked ornithine turn connecting positions 17 and 36 to create a macrocycle and an intramolecular disulfide linkage between positions 24 and 29. An N-methyl group at position 33 blocks uncontrolled aggregation. The peptide readily crystallizes as a folded ?-hairpin, which assembles hierarchically in the crystal lattice. Three ?-hairpin monomers assemble to form a triangular trimer, four trimers assemble in a tetrahedral arrangement to form a dodecamer, and five dodecamers pack together to form an annular pore. This hierarchical assembly provides a model, in which full-length A? transitions from an unfolded monomer to a folded ?-hairpin, which assembles to form oligomers that further pack to form an annular pore. This model may provide a better understanding of the molecular basis of Alzheimer's disease at atomic resolution.

| S-EPMC4831588 | biostudies-literature

A Hexamer of a Peptide Derived from A?16-36.

Project description:The absence of high-resolution structures of amyloid oligomers constitutes a major gap in our understanding of amyloid diseases. A growing body of evidence indicates that oligomers of the ?-amyloid peptide A? are especially important in the progression of Alzheimer's disease. In many A? oligomers, the A? monomer components are thought to adopt a ?-hairpin conformation. This paper describes the design and study of a macrocyclic ?-hairpin peptide derived from A?16-36. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and size exclusion chromatography studies show that the A?16-36 ?-hairpin peptide assembles in solution to form hexamers, trimers, and dimers. X-ray crystallography reveals that the peptide assembles to form a hexamer in the crystal state and that the hexamer is composed of dimers and trimers. Lactate dehydrogenase release assays show that the oligomers formed by the A?16-36 ?-hairpin peptide are toxic toward neuronally derived SH-SY5Y cells. Replica-exchange molecular dynamics demonstrates that the hexamer can accommodate full-length A?. These findings expand our understanding of the structure, solution-phase behavior, and biological activity of A? oligomers and may offer insights into the molecular basis of Alzheimer's disease.

| S-EPMC5689071 | biostudies-literature

X-ray crystallographic structures of trimers and higher-order oligomeric assemblies of a peptide derived from Aβ(17-36).

Project description:A peptide derived from Aβ17-36 crystallizes to form trimers that further associate to form higher-order oligomers. The trimers consist of three highly twisted β-hairpins in a triangular arrangement. Two trimers associate face-to-face in the crystal lattice to form a hexamer; four trimers in a tetrahedral arrangement about a central cavity form a dodecamer. These structures provide a working model for the structures of oligomers associated with neurodegeneration in Alzheimer's disease.

| S-EPMC4004244 | biostudies-literature

X-ray Crystallographic Structure of α-Helical Peptide Stabilized by Hydrocarbon Stapling at i,i + 1 Positions.

Project description:Hydrocarbon stapling is a useful tool for stabilizing the secondary structure of peptides. Among several methods, hydrocarbon stapling at i,i + 1 positions was not extensively studied, and their secondary structures are not clarified. In this study, we investigate i,i + 1 hydrocarbon stapling between cis-4-allyloxy-l-proline and various olefin-tethered amino acids. Depending on the ring size of the stapled side chains and structure of the olefin-tethered amino acids, E- or Z-selectivities were observed during the ring-closing metathesis reaction (E/Z was up to 8.5:1 for 17-14-membered rings and up to 1:20 for 13-membered rings). We performed X-ray crystallographic analysis of hydrocarbon stapled peptide at i,i + 1 positions. The X-ray crystallographic structure suggested that the i,i + 1 staple stabilizes the peptide secondary structure to the right-handed α-helix. These findings are especially important for short oligopeptides because the employed stapling method uses two minimal amino acid residues adjacent to each other.

| S-EPMC8160927 | biostudies-literature

Effects of Familial Alzheimer's Disease Mutations on the Assembly of a β-Hairpin Peptide Derived from Aβ16-36.

Project description:Familial Alzheimer's disease (FAD) is associated with mutations in the β-amyloid peptide (Aβ) or the amyloid precursor protein (APP). FAD mutations of Aβ were incorporated into a macrocyclic peptide that mimics a β-hairpin to study FAD point mutations K16N, A21G, E22Δ, E22G, E22Q, E22K, and L34V and their effect on assembly, membrane destabilization, and cytotoxicity. The X-ray crystallographic structures of the four E22 mutant peptides reveal that the peptides assemble to form the same compact hexamer. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) experiments reveal that the mutant FAD peptides assemble as trimers or hexamers, with peptides that have greater positive charge assembling as more stable hexamers. Mutations that increase the positive charge also increase the cytotoxicity of the peptides and their propensity to destabilize lipid membranes.

| S-EPMC9042424 | biostudies-literature

X-ray Crystallographic Structure and Oligomerization of Gloeobacter Rhodopsin.

Project description:Gloeobacter rhodopsin (GR) is a cyanobacterial proton pump which can be potentially applied to optogenetics. We solved the crystal structure of GR and found that it has overall similarity to the homologous proton pump from Salinibacter ruber, xanthorhodopsin (XR). We identified distinct structural characteristics of GR's hydrogen bonding network in the transmembrane domain as well as the displacement of extracellular sides of the transmembrane helices relative to those of XR. Employing Raman spectroscopy and flash-photolysis, we found that GR in the crystals exists in a state which displays retinal conformation and photochemical cycle similar to the functional form observed in lipids. Based on the crystal structure of GR, we selected a site for spin labeling to determine GR's oligomerization state using double electron-electron resonance (DEER) spectroscopy and demonstrated the pH-dependent pentamer formation of GR. Determination of the structure of GR as well as its pentamerizing propensity enabled us to reveal the role of structural motifs (extended helices, 3-omega motif and flipped B-C loop) commonly found among light-driven bacterial pumps in oligomer formation. Here we propose a new concept to classify these pumps based on the relationship between their oligomerization propensities and these structural determinants.

| S-EPMC6677831 | biostudies-literature

X-ray crystallographic structure of an artificial beta-sheet dimer.

Project description:This paper describes the X-ray crystallographic structure of a designed cyclic beta-sheet peptide that forms a well-defined hydrogen-bonded dimer that mimics beta-sheet dimers formed by proteins. The 54-membered ring macrocyclic peptide (1a) contains molecular template and turn units that induce beta-sheet structure in a heptapeptide strand that forms the dimerization interface. The X-ray crystallographic structure reveals the structures of the two "Hao" amino acids that help template the beta-sheet structure and the two delta-linked ornithine turn units that link the Hao-containing template to the heptapeptide beta-strand. The Hao amino acids adopt a conformation that resembles a tripeptide in a beta-strand conformation, with one edge of the Hao unit presenting an alternating array of hydrogen-bond donor and acceptor groups in the same pattern as that of a tripeptide beta-strand. The delta-linked ornithines adopt a conformation that resembles a hydrogen-bonded beta-turn, in which the ornithine takes the place of the i+1 and i+2 residues. The dimers formed by macrocyclic beta-sheet 1a resemble the dimers of many proteins, such as defensin HNP-3, the lambda-Cro repressor, interleukin 8, and the ribonuclease H domain of HIV-1 reverse transcriptase. The dimers of 1a self-assemble in the solid state into a barrel-shaped trimer of dimers in which the three dimers are arranged in a triangular fashion. Molecular modeling in which one of the three dimers is removed and the remaining two dimers are aligned face-to-face provides a model of the dimers of dimers of closely related macrocyclic beta-sheet peptides that were observed in solution.

| S-EPMC2929266 | biostudies-literature

X-ray Crystallographic Structures of Oligomers of Peptides Derived from β2-Microglobulin.

Project description:Amyloid diseases such as Alzheimer's disease, Parkinson's disease, and type II diabetes share common features of toxic soluble protein oligomers. There are no structures at atomic resolution of oligomers formed by full-length amyloidogenic peptides and proteins, and only a few structures of oligomers formed by peptide fragments. The paucity of structural information provides a fundamental roadblock to understanding the pathology of amyloid diseases and developing preventions or therapies. Here, we present the X-ray crystallographic structures of three families of oligomers formed by macrocyclic peptides containing a heptapeptide sequence derived from the amyloidogenic E chain of β2-microglobulin (β2m). Each macrocyclic peptide contains the heptapeptide sequence β2m63-69 and a second heptapeptide sequence containing an N-methyl amino acid. These peptides form β-sheets that further associate into hexamers, octamers, and dodecamers: the hexamers are trimers of dimers; the octamers are tetramers of dimers; and the dodecamers contain two trimer subunits surrounded by three pairs of β-sheets. These structures illustrate a common theme in which dimer and trimer subunits further associate to form a hydrophobic core. The seven X-ray crystallographic structures not only illustrate a range of oligomers that a single amyloidogenic peptide sequence can form, but also how mutation can alter the size and topology of the oligomers. A cocrystallization experiment in which a dodecamer-forming peptide recruits a hexamer-forming peptide to form mixed dodecamers demonstrates that one species can dictate the oligomerization of another. These findings should also be relevant to the formation of oligomers of full-length peptides and proteins in amyloid diseases.

| S-EPMC4523215 | biostudies-literature

X-ray Crystallography Reveals Parallel and Antiparallel β-Sheet Dimers of a β-Hairpin Derived from Aβ16-36 that Assemble to Form Different Tetramers.

Project description:High-resolution structures of oligomers formed by the β-amyloid peptide, Aβ, are important for understanding the molecular basis of Alzheimer's disease. Dimers of Aβ are linked to the pathogenesis and progression of Alzheimer's disease, and tetramers of Aβ are neurotoxic. This paper reports the X-ray crystallographic structures of dimers and tetramers, as well as an octamer, formed by a peptide derived from the central and C-terminal regions of Aβ. In the crystal lattice, the peptide assembles to form two different dimers-an antiparallel β-sheet dimer and a parallel β-sheet dimer-that each further self-assemble to form two different tetramers-a sandwich-like tetramer and a twisted β-sheet tetramer. The structures of these dimers and tetramers derived from Aβ serve as potential models for dimers and tetramers of full-length Aβ that form in vitro and in Alzheimer's disease-afflicted brains.

| S-EPMC7811405 | biostudies-literature