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Chemical Cross-Linking/Mass Spectrometry Maps the Amyloid β Peptide Binding Region on Both Apolipoprotein E Domains

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Chemical Cross-Linking/Mass Spectrometry Maps the Amyloid β Peptide Binding Region on Both Apolipoprotein E Domains

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DEROO, Stéphanie, Florian STENGEL, Azadeh MOHAMMADI, Nicolas HENRY, Ellen HUBIN, Eva-Maria KRAMMER, Ruedi AEBERSOLD, Vincent RAUSSENS, 2015. Chemical Cross-Linking/Mass Spectrometry Maps the Amyloid β Peptide Binding Region on Both Apolipoprotein E Domains. In: ACS Chemical Biology. 10(4), pp. 1010-1016. ISSN 1554-8929. eISSN 1554-8937. Available under: doi: 10.1021/cb500994j

@article{Deroo2015Chemi-31886, title={Chemical Cross-Linking/Mass Spectrometry Maps the Amyloid β Peptide Binding Region on Both Apolipoprotein E Domains}, year={2015}, doi={10.1021/cb500994j}, number={4}, volume={10}, issn={1554-8929}, journal={ACS Chemical Biology}, pages={1010--1016}, author={Deroo, Stéphanie and Stengel, Florian and Mohammadi, Azadeh and Henry, Nicolas and Hubin, Ellen and Krammer, Eva-Maria and Aebersold, Ruedi and Raussens, Vincent} }

Deroo, Stéphanie Henry, Nicolas Mohammadi, Azadeh 2015-10-02T12:33:49Z Mohammadi, Azadeh Apolipoprotein E (apoE) binds the amyloid β peptide (Aβ), one of the major culprits in Alzheimer’s disease development. The formation of apoE:Aβ complexes is implicated in both Aβ clearance and fibrillization. However, the binding interface between apoE and Aβ is poorly defined despite substantial previous research efforts, and the exact role of apoE in the pathology of Alzheimer’s disease remains largely elusive. Here, we compared the three main isoforms of apoE (E2, E3, and E4) for their interaction with Aβ<sub>1–42</sub> in an early stage of aggregation and at near physiological conditions. Using electron microscopy and Western blots, we showed that all three isoforms are able to prevent Aβ fibrillization and form a noncovalent complex, with one molecule of Aβ bound per apoE. Using chemical cross-linking coupled to mass spectrometry, we further examined the interface of interaction between apoE2/3/4 and Aβ. Multiple high-confidence intermolecular apoE2/3/4:Aβ cross-links confirmed that Lys16 is located in the region of Aβ binding to apoE2/3/4. Further, we demonstrated that both N- and C-terminal domains of apoE2/3/4 are interacting with Aβ. The cross-linked sites were mapped onto and evaluated in light of a recent structure of apoE. Our results support binding of the hydrophobic Aβ at the apoE domain–domain interaction interface, which would explain how apoE is able to stabilize Aβ and thereby prevent its subsequent aggregation. Raussens, Vincent Aebersold, Ruedi Henry, Nicolas Aebersold, Ruedi Krammer, Eva-Maria Hubin, Ellen Krammer, Eva-Maria 2015 Deroo, Stéphanie Stengel, Florian Chemical Cross-Linking/Mass Spectrometry Maps the Amyloid β Peptide Binding Region on Both Apolipoprotein E Domains Stengel, Florian Hubin, Ellen Raussens, Vincent 2015-10-02T12:33:49Z eng

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