Conversion of Abeta42 into a folded soluble native-like protein using a semi-random library of amphipathic helices
- PMID: 20026077
- DOI: 10.1016/j.jmb.2009.12.019
Conversion of Abeta42 into a folded soluble native-like protein using a semi-random library of amphipathic helices
Abstract
The amyloid cascade model hypothesizes that neurotoxic oligomers or aggregates formed by the Alzheimer amyloid peptide (Abeta) cause disease pathology in Alzheimer's disease. Attempted treatment strategies for Alzheimer's disease have involved either inhibiting Abeta oligomerization or aggregation, or dissolving existing aggregates. Blocking such downhill processes, however, has proved daunting. We have used a different approach that targets Abeta before the oligomerization cascade begins. We predicted that an amphipathic helix could convert Abeta into a native-like protein and inhibit initiation of oligomerization and aggregation. This idea was tested with a designed library and genetic screen. We exhaustively screened a library of semi-randomized amphipathic helical sequences, each expressed as a fusion protein with an Abeta42-yellow fluorescent protein sequence serving as a reporter for folding and solubilization. This yielded an amphipathic helix capable of initiating native-like folding in Abeta42 and preventing aggregation. This amphipathic helix has direct application to Alzheimer's disease therapy development.
Copyright (c) 2009 Elsevier Ltd. All rights reserved.
Similar articles
-
Mutations that reduce aggregation of the Alzheimer's Abeta42 peptide: an unbiased search for the sequence determinants of Abeta amyloidogenesis.J Mol Biol. 2002 Jun 21;319(5):1279-90. doi: 10.1016/S0022-2836(02)00399-6. J Mol Biol. 2002. PMID: 12079364
-
Probing Alzheimer amyloid peptide aggregation using a cell-free fluorescent protein refolding method.Biochem Cell Biol. 2009 Aug;87(4):631-9. doi: 10.1139/o09-038. Biochem Cell Biol. 2009. PMID: 19767826
-
Direct in vivo intracellular selection of conformation-sensitive antibody domains targeting Alzheimer's amyloid-beta oligomers.J Mol Biol. 2009 Apr 3;387(3):584-606. doi: 10.1016/j.jmb.2009.01.061. Epub 2009 Feb 4. J Mol Biol. 2009. PMID: 19361429
-
Computational prediction and redesign of aberrant protein oligomerization.Prog Mol Biol Transl Sci. 2020;169:43-83. doi: 10.1016/bs.pmbts.2019.11.002. Epub 2019 Dec 20. Prog Mol Biol Transl Sci. 2020. PMID: 31952691 Review.
-
Introduction and technical survey: protein aggregation and fibrillogenesis.Subcell Biochem. 2012;65:3-25. doi: 10.1007/978-94-007-5416-4_1. Subcell Biochem. 2012. PMID: 23224997 Review.
Cited by
-
Common features at the start of the neurodegeneration cascade.PLoS Biol. 2012;10(5):e1001335. doi: 10.1371/journal.pbio.1001335. Epub 2012 May 29. PLoS Biol. 2012. PMID: 22666178 Free PMC article.
-
Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses.Sci Rep. 2016 Apr 28;6:25080. doi: 10.1038/srep25080. Sci Rep. 2016. PMID: 27122057 Free PMC article.
-
Rapid α-oligomer formation mediated by the Aβ C terminus initiates an amyloid assembly pathway.Nat Commun. 2016 Aug 22;7:12419. doi: 10.1038/ncomms12419. Nat Commun. 2016. PMID: 27546208 Free PMC article.
-
Techniques for Monitoring Protein Misfolding and Aggregation in Vitro and in Living Cells.Korean J Chem Eng. 2012 Jun;29(6):693-702. doi: 10.1007/s11814-012-0060-x. Korean J Chem Eng. 2012. PMID: 23565019 Free PMC article.
-
Recent Advances in the Application Peptide and Peptoid in Diagnosis Biomarkers of Alzheimer's Disease in Blood.Front Mol Neurosci. 2021 Dec 23;14:778955. doi: 10.3389/fnmol.2021.778955. eCollection 2021. Front Mol Neurosci. 2021. PMID: 35002620 Free PMC article. Review.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources