Key residues for the oligomerization of Aβ42 protein in Alzheimer’s disease

Ngo, Sam; Guo, Zhefeng

doi:10.1016/j.bbrc.2011.09.097

Cited by 30 publications

(44 citation statements)

References 40 publications

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“…For these reasons, we conclude that the SDS-resistant GU-A␤42 oligomers are tetramers and hexamers. This finding is similar to our previous study showing that GU-A␤42 oligomers also form tetramers and hexamers in the presence of 8 M urea (38). Here the oligomer sample contains only 0.4 M urea.…”

Section: A␤42 Fusion Protein Forms A11-positive Prefibrillarsupporting

confidence: 82%

“…Mutations were confirmed with DNA sequencing. Expression of GroES-ubiquitin-A␤42 in E. coli and their purification were performed as previously described in Ngo and Guo (38). Expression of Usp2cc and removal of fusion protein GU to prepare full-length A␤42 was performed as previously described in Gu et al (39).…”

Section: Preparation Of A␤42 Fusion Proteins and Full-length A␤42-mentioning

confidence: 99%

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Antiparallel Triple-strand Architecture for Prefibrillar Aβ42 Oligomers

Liu

Stroud

et al. 2014

Journal of Biological Chemistry

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Background: Soluble A␤42 oligomers, rather than insoluble amyloid fibrils, are toxic species in Alzheimer's disease. Results: We obtained structural restraints at all 42 residue positions in A␤42 oligomers and performed structural modeling. Conclusion: In oligomers, each A␤42 protein forms a single ␤-sheet with three antiparallel ␤-strands. Significance: Our novel structural model provides new structural framework for understanding oligomer-fibril interconversion and designing oligomer-targeted therapeutics.

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Section: A␤42 Fusion Protein Forms A11-positive Prefibrillarsupporting

confidence: 82%

Section: Preparation Of A␤42 Fusion Proteins and Full-length A␤42-mentioning

confidence: 99%

Antiparallel Triple-strand Architecture for Prefibrillar Aβ42 Oligomers

Liu

Stroud

et al. 2014

Journal of Biological Chemistry

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“…55 In addition, Leu34 is found to be packing with Phe19 in both oligomer and fibril models. 56 We find that the side chain of Leu34 is exposed only 39% of the time to solvent, and the binding of NQTrp prevents Leu34 from interacting with Phe19.…”

Section: ■ Discussionmentioning

confidence: 95%

Atomic and Dynamic Insights into the Beneficial Effect of the 1,4-Naphthoquinon-2-yl-l-tryptophan Inhibitor on Alzheimer’s Aβ1–42 Dimer in Terms of Aggregation and Toxicity

Zhang

et al. 2013

ACS Chem. Neurosci.

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Aggregation of the amyloid β protein (Aβ) peptide with 40 or 42 residues is one key feature in Alzheimer's disease (AD). The 1,4-naphthoquinon-2-yl-L-tryptophan (NQTrp) molecule was reported to alter Aβ self-assembly and reduce toxicity. Though nuclear magnetic resonance experiments and various simulations provided atomic information about the interaction of NQTrp with Aβ peptides spanning the regions of residues 12−28 and 17−42, none of these studies were conducted on the fulllength Aβ1−42 peptide. To this end, we performed extensive atomistic replica exchange molecular dynamics simulations of Aβ1−42 dimer with two NQTrp molecules in explicit solvent, by using a force field known to fold diverse proteins correctly. The interactions between NQTrp and Aβ1−42, which change the Aβ interface by reducing most of the intermolecular contacts, are found to be very dynamic and multiple, leading to many transient binding sites. The most favorable binding residues are Arg5, Asp7, Tyr10, His13, Lys16, Lys18, Phe19/Phe20, and Leu34/Met35, providing therefore a completely different picture from in vitro and in silico experiments with NQTrp with shorter Aβ fragments. Importantly, the 10 hot residues that we identified explain the beneficial effect of NQTrp in reducing both the level of Aβ1−42 aggregation and toxicity. Our results also indicate that there is room to design more efficient drugs targeting Aβ1−42 dimer against AD.

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“…The cells were cultured to an absorbance of A 600 nm Ϸ0.6 in LB broth at 37°C and then induced with 1 mM IPTG at 28°C for 4 -6 h. A␤ fusion protein was purified using a nickel column as previously described (35). For purification of Usp2cc, the cells were resuspended in TG buffer (50 mM Tris, 5 mM ␤-mecaptoethanol, 30% glycerol, pH 7.5) and then sonicated on ice.…”

Section: Methodsmentioning

confidence: 99%

Solid-support Electron Paramagnetic Resonance (EPR) Studies of Aβ40 Monomers Reveal a Structured State with Three Ordered Segments

Ngo

Guo

2012

Journal of Biological Chemistry

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Background: A␤ monomer is the building block of neurotoxic oligomers in Alzheimer disease. Results: EPR studies of A␤40 monomers tethered on solid support show lower spin label mobility at residues 14 -18, 29 -30, and 38 -40. Conclusion: A␤40 monomer adopts a structured state with three ordered segments at 14 -18, 29 -30, and 38 -40. Significance: Structural information of A␤40 monomer is crucial for understanding the mechanism of A␤ oligomerization.

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Key residues for the oligomerization of Aβ42 protein in Alzheimer’s disease

Cited by 30 publications

References 40 publications

Antiparallel Triple-strand Architecture for Prefibrillar Aβ42 Oligomers

Antiparallel Triple-strand Architecture for Prefibrillar Aβ42 Oligomers

Atomic and Dynamic Insights into the Beneficial Effect of the 1,4-Naphthoquinon-2-yl-l-tryptophan Inhibitor on Alzheimer’s Aβ1–42 Dimer in Terms of Aggregation and Toxicity

Solid-support Electron Paramagnetic Resonance (EPR) Studies of Aβ40 Monomers Reveal a Structured State with Three Ordered Segments

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