1. Structural changes of region 1-16 of the Alzheimer disease amyloid beta-peptide upon zinc binding and in vitro aging
Sergey A Kozin,Pascale Debey,Sylvie Rebuffat,Michel Cheminant,Séverine Zirah,Alain Blond,Alexey K Mazur,Isabelle Ségalas-Milazzo J Biol Chem . 2006 Jan 27;281(4):2151-61. doi: 10.1074/jbc.M504454200.
Amyloid deposits within the cerebral tissue constitute a characteristic lesion associated with Alzheimer disease. They mainly consist of the amyloid peptide Abeta and display an abnormal content in Zn(2+) ions, together with many truncated, isomerized, and racemized forms of Abeta. The region 1-16 of Abeta can be considered the minimal zinc-binding domain and contains two aspartates subject to protein aging. The influence of zinc binding and protein aging related modifications on the conformation of this region of Abeta is of importance given the potentiality of this domain to constitute a therapeutic target, especially for immunization approaches. In this study, we determined from NMR data the solution structure of the Abeta-(1-16)-Zn(2+) complex in aqueous solution at pH 6.5. The residues His(6), His(13), and His(14) and the Glu(11) carboxylate were identified as ligands that tetrahedrally coordinate the Zn(II) cation. In vitro aging experiments on Abeta-(1-16) led to the formation of truncated and isomerized species. The major isomer generated, Abeta-(1-16)-l-iso-Asp(7), displayed a local conformational change in the His(6)-Ser(8) region but kept a zinc binding propensity via a coordination mode involving l-iso-Asp(7). These results are discussed here with regard to Abeta fibrillogenesis and the potentiality of the region 1-16 of Abeta to be used as a therapeutic target.
2. Studies on Copper and Aβ 1-16-Induced Conformational Changes in CAG/CTG Trinucleotide Repeats Sequence
D Jagadeesh Kumar,K S Rao Jayanth,U J S Prasada Rao,K R S Sambasiva Rao,M Govindaraju,K S Rao J Alzheimers Dis Rep . 2017 Dec 29;1(1):277-286. doi: 10.3233/ADR-170027.
DNA conformation and stability are critical for the normal cell functions, which control many cellular processes in life, such as replication, transcription, DNA repair, etc. The accumulation of amyloid-β peptide (Aβ) and Copper (Cu) are the etiological factors for neurodegenerative diseases and hypothesized that they can cause DNA instability. In the current investigation, we studied copper and Aβ1-16induced conformation and stability changes in CAG/CTG sequences and found alterations from B-DNA to altered B-conformation. Further, the interaction of the copper and Aβ1-16with CAG/CTG sequences was studied by molecular docking modeling and results indicated that the interaction of copper and Aβ1-16was through the hydrogen bond formation between adenine, guanine, and cytocine. This study illustrates the role of the copper and Aβ1-16in modulating the DNA conformation and stability.
3. Structural properties of amyloid β(1-40) dimer explored by replica exchange molecular dynamics simulations
Sándor Lovas,Cole P Frisbie,Charles R Watts,Andrew J Gregory Proteins . 2017 Jun;85(6):1024-1045. doi: 10.1002/prot.25270.
Replica exchange molecular dynamics simulations (300 ns) were used to study the dimerization of amyloid β(1-40) (Aβ(1-40)) polypeptide. Configurational entropy calculations revealed that at physiological temperature (310 K, 37°C) dynamic dimers are formed by randomly docked monomers. Free energy of binding of the two chains to each other was -93.56 ± 6.341 kJ mol-1. Prevalence of random coil conformations was found for both chains with the exceptions of increased β-sheet content from residues 16-21 and 29-32 of chain A and residues 15-21 and 30-33 of chain B with β-turn/β-bend conformations in both chains from residues 1-16, 21-29 of chain A, 1-16, and 21-29 of chain B. There is a mixed β-turn/β-sheet region from residues 33-38 of both chains. Analysis of intra- and interchain residue distances shows that, although the individual chains are highly flexible, the dimer system stays in a loosely packed antiparallel β-sheet configuration with contacts between residues 17-21 of chain A with residues 17-21 and 31-36 of chain B as well as residues 31-36 of chain A with residues 17-21 and 31-36 of chain B. Based on dihedral principal component analysis, the antiparallel β-sheet-loop-β-sheet conformational motif is favored for many low energy sampled conformations. Our results show that Aβ(1-40) can form dynamic dimers in aqueous solution that have significant conformational flexibility and are stabilized by collapse of the central and C-terminal hydrophobic cores with the expected β-sheet-loop-β-sheet conformational motif. Proteins 2017; 85:1024-1045. © 2017 Wiley Periodicals, Inc.
4. The metal loading ability of beta-amyloid N-terminus: a combined potentiometric and spectroscopic study of copper(II) complexes with beta-amyloid(1-16), its short or mutated peptide fragments, and its polyethylene glycol (PEG)-ylated analogue
Chiara A Damante,Enrico Rizzarelli,Imre Sóvágó,Giulia Grasso,Giuseppe Pappalardo,Katalin Osz,Zoltán Nagy,Giuseppe Impellizzeri Inorg Chem . 2008 Oct 20;47(20):9669-83. doi: 10.1021/ic8006052.
Alzheimer's disease (AD) is becoming a rapidly growing health problem, as it is one of the main causes of dementia in the elderly. Interestingly, copper(II) (together with zinc and iron) ions are accumulated in amyloid deposits, suggesting that metal binding to Abeta could be involved in AD pathogenesis. In Abeta, the metal binding is believed to occur within the N-terminal region encompassing the amino acid residues 1-16. In this work, potentiometric, spectroscopic (UV-vis, circular dichroism, and electron paramagnetic resonance), and electrospray ionization mass spectrometry (ESI-MS) approaches were used to investigate the copper(II) coordination features of a new polyethylene glycol (PEG)-conjugated Abeta peptide fragment encompassing the 1-16 amino acid residues of the N-terminal region (Abeta(1-16)PEG). The high water solubility of the resulting metal complexes allowed us to obtain a complete complex speciation at different metal-to-ligand ratios ranging from 1:1 to 4:1. Potentiometric and ESI-MS data indicate that Abeta(1-16)PEG is able to bind up to four copper(II) ions. Furthermore, in order to establish the coordination environment at each metal binding site, a series of shorter peptide fragments of Abeta, namely, Abeta(1-4), Abeta(1-6), AcAbeta(1-6), and AcAbeta(8-16)Y10A, were synthesized, each encompassing a potential copper(II) binding site. The complexation properties of these shorter peptides were also comparatively investigated by using the same experimental approach.