The β amyloid peptide can act as a modular aggregation domain

Link, Christopher D.; Fonte, Virginia; Roberts, Christine M.; Hiester, Brian G.; Silverman, Michael; Stein, Gretchen H.

doi:10.1016/j.nbd.2008.08.003

Cited by 8 publications

(7 citation statements)

References 36 publications

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“…We have previously shown that the Aβ sequence can act as a modular aggregation domain, such that the C-terminal addition of Aβ 3-42 to GFP converts this normally soluble protein to a strongly aggregating one [ 20 ]. Introduction of an L17P substitution into the Aβ sequence reverses this aggregation capacity, thus GFP::Aβ L17P is soluble when expressed in C. elegans or hippocampal neurons.…”

Section: Resultsmentioning

confidence: 99%

A glycine zipper motif mediates the formation of toxic β-amyloid oligomers in vitro and in vivo

Fonte

Dostal

Roberts

et al. 2011

Mol Neurodegeneration

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BackgroundThe β-amyloid peptide (Aβ) contains a Gly-XXX-Gly-XXX-Gly motif in its C-terminal region that has been proposed to form a "glycine zipper" that drives the formation of toxic Aβ oligomers. We have tested this hypothesis by examining the toxicity of Aβ variants containing substitutions in this motif using a neuronal cell line, primary neurons, and a transgenic C. elegans model.ResultsWe found that a Gly37Leu substitution dramatically reduced Aβ toxicity in all models tested, as measured by cell dysfunction, cell death, synaptic alteration, or tau phosphorylation. We also demonstrated in multiple models that Aβ Gly37Leu is actually anti-toxic, thereby supporting the hypothesis that interference with glycine zipper formation blocks assembly of toxic Aβ oligomers. To test this model rigorously, we engineered second site substitutions in Aβ predicted by the glycine zipper model to compensate for the Gly37Leu substitution and expressed these in C. elegans. We show that these second site substitutions restore in vivo Aβtoxicity, further supporting the glycine zipper model.ConclusionsOur structure/function studies support the view that the glycine zipper motif present in the C-terminal portion of Aβ plays an important role in the formation of toxic Aβ oligomers. Compounds designed to interfere specifically with formation of the glycine zipper could have therapeutic potential.

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Section: Resultsmentioning

confidence: 99%

A glycine zipper motif mediates the formation of toxic β-amyloid oligomers in vitro and in vivo

Fonte

Dostal

Roberts

et al. 2011

Mol Neurodegeneration

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“…Recently, GFP molecule has also been used as a reporting protein in fusion constructs with A peptides for visualizing A oligomers in vivo [39]. However, in these and other studies [40][41][42][43], the impact of linker length on oligomerization or fibril formation was not evaluated. Although some GFPs have a weak dimerization tendency, if necessary, monomeric GFPs can be easily obtained by the dimer interface breaking mutations [44].…”

Section: Choice Of a Modelmentioning

confidence: 99%

Establishment of Constraints on Amyloid Formation Imposed by Steric Exclusion of Globular Domains

Azizyan

Garro

Radkova

et al. 2018

Journal of Molecular Biology

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In many disease-related and functional amyloids, the amyloid-forming regions of proteins are flanked by globular domains. When located in close vicinity of the amyloid regions along the chain, the globular domains can prevent the formation of amyloids because of the steric repulsion. Experimental tests of this effect are few in number and non-systematic, and their interpretation is hampered by polymorphism of amyloid structures. In this situation, modeling approaches that use such a clear-cut criterion as the steric tension can give us highly trustworthy results. In this work, we evaluated this steric effect by using molecular modeling and dynamics. As an example, we tested hybrid proteins containing an amyloid-forming fragment of Aβ peptide (17-42) linked to one or two globular domains of GFP. Searching for the shortest possible linker, we constructed models with pseudo-helical arrangements of the densely packed GFPs around the Aβ amyloid core. The molecular modeling showed that linkers of 7 and more residues allow fibrillogenesis of the Aβ-peptide flanked by GFP on one side and 18 and more residues when Aβ-peptide is flanked by GFPs on both sides. Furthermore, we were able to establish a more general relationship between the size of the globular domains and the length of the linkers by using analytical expressions and rigid body simulations. Our results will find use in planning and interpretation of experiments, improvement of the prediction of amyloidogenic regions in proteins, and design of new functional amyloids carrying globular domains.

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“…SDS-PAGE and immunoblotting were performed as previously described (23). Briefly, 20 mg protein were loaded per lane and SDS-PAGE was performed using NuPAGE 4 -12% Bis-Tris Gel (Invitrogen, catalogue number NP0321).…”

Section: Immunoblottingmentioning

confidence: 99%

AIP-1 ameliorates β-amyloid peptide toxicity in a Caenorhabditis elegans Alzheimer's disease model

Hassan

Merin

Fonte

et al. 2009

Human Molecular Genetics

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Multiple neurodegenerative diseases are causally linked to aggregation-prone proteins. Cellular mechanisms involving protein turnover may be key defense mechanisms against aggregating protein disorders. We have used a transgenic Caenorhabditis elegans Alzheimer's disease model to identify cellular responses to proteotoxicity resulting from expression of the human beta amyloid peptide (Abeta). We show up-regulation of aip-1 in Abeta-expressing animals. Mammalian homologues of AIP-1 have been shown to associate with, and regulate the function of, the 26S proteasome, leading us to hypothesize that induction of AIP-1 may be a protective cellular response directed toward modulating proteasomal function in response to toxic protein aggregation. Using our transgenic model, we show that overexpression of AIP-1 protected against, while RNAi knockdown of AIP-1 exacerbated, Abeta toxicity. AIP-1 overexpression also reduced accumulation of Abeta in this model, which is consistent with AIP-1 enhancing protein degradation. Transgenic expression of one of the two human aip-1 homologues (AIRAPL), but not the other (AIRAP), suppressed Abeta toxicity in C. elegans, which advocates the biological relevance of the data to human biology. Interestingly, AIRAPL and AIP-1 contain a predicted farnesylation site, which is absent from AIRAP. This farnesylation site was shown by others to be essential for an AIP-1 prolongevity function. Consistent with this, we show that an AIP-1 mutant lacking the predicted farnesylation site failed to protect against Abeta toxicity. Our results implicate AIP-1 in the regulation of protein turnover and protection against Abeta toxicity and point at AIRAPL as the functional mammalian homologue of AIP-1.

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The β amyloid peptide can act as a modular aggregation domain

Cited by 8 publications

References 36 publications

A glycine zipper motif mediates the formation of toxic β-amyloid oligomers in vitro and in vivo

A glycine zipper motif mediates the formation of toxic β-amyloid oligomers in vitro and in vivo

Establishment of Constraints on Amyloid Formation Imposed by Steric Exclusion of Globular Domains

AIP-1 ameliorates β-amyloid peptide toxicity in a Caenorhabditis elegans Alzheimer's disease model

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