Abstract
Several lines of evidence point to the important role of the N-terminal region of amyloid-beta (Aβ) peptide in its toxic aggregation in Alzheimer’s disease (AD). It is known that charge-altering modifications such as Ser8 phosphorylation promote Aβ fibrillar aggregation. In this Letter, we combine high-pressure NMR, multiquantum chemical exchange saturation transfer (MQ-CEST) NMR, and microseconds-long molecular dynamics simulation and provide evidence of the presence of several salt bridges between Arg5 and its nearby negatively charged residues, in particular, Asp7 and Glu3. The presence of these salt bridges is correlated with less extended structures in the N-terminal region of Aβ. Through density functional theory calculations, we demonstrate how the introduction of negatively charged phosphoserine 8 influences the network of adjacent salt bridges in Aβ and favors more extended N-terminal structures. Our data propose a structural mechanism for the Ser8-phosphorylation-promoted Aβ aggregation and define the N-terminal salt bridges as potential targets for anti-AD drug design.
Highlights
Several lines of evidence point to the important role of the N-terminal region of amyloid-beta (Aβ) peptide in its toxic aggregation in Alzheimer’s disease (AD)
The N-terminal region of Aβ, that is, residues 1−10, is the host for several AD-related mutations, such as A2V, H6R, and D7N mutations,[12−14] and modifications, such as N-terminal truncation, S8 phosphorylation, and Y10 nitration,[15−17] which alter its aggregation propensity. Because this region appears to be relatively unstructured in Aβ fibrils,[18] the altered aggregation behavior of Aβ upon its N-terminal modifications suggests that the N-terminal region of Aβ may play an important role in the intermediate stages of Aβ aggregation
High-pressure NMR studies of several amyloidogenic proteins have proven useful in detecting and structurally characterizing their conformational substates and correlating them with their distinct aggregation propensities.[24−28] Here we study the structural dynamics of Aβ dependent on pressure with a focus on its Nterminal region
Summary
S6.) When compared with the control group, the test group containing Arg5-based salt bridges was relatively destabilized upon Ser[8] phosphorylation, especially when both the Arg5-Asp[7] and Arg5-Glu[3] salt bridges were present (Table 1). The presence of a relatively compact (sub)ensemble of Aβ monomers in rapid exchange with largely unstructured Aβ monomers has been previously shown.[24] It is expected that the partial disruption of the Nterminal salt bridges caused by Ser8-phosphorylation, as proposed by our DFT calculations, induces a relatively mobile extended structure in the N-terminal region of Aβ and enables the long-range interactions between the N-terminus and the rest of amyloid core observed in pSer8-Aβ fibrils.[37,38] it is notable that the brain-derived Aβ fibrils contain Arg5-Glu[3] salt bridges between adjacent protofibrils, suggesting that the Arg5-based salt bridges may play a role in the higher order assembly of Aβ aggregates as well.[22] our results put forward the hypothesis that the network of electrostatic interactions in the N-terminal region of Aβ may act as a regulatory switch in Aβ aggregation.
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