Side-chain moieties from the N-terminal region of Aβ are Involved in an oligomer-stabilizing network of interactions

Kaja Przygońska, Jarosław Poznański, Ulrik H. Mistarz, Kasper D. Rand, Michał Dadlez

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

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Abstract

Oligomeric forms of the Aβ peptide represent the most probable neurotoxic agent in Alzheimer’s disease. The dynamic and heterogeneous character of these oligomers makes their structural characterization by classic methods difficult. Native mass spectrometry, when supported by additional gas phase techniques, like ion mobility separation and hydrogen-deuterium exchange (IM-HDX-MS), enable analysis of different oligomers coexisting in the sample and may provide species-specific structural information for each oligomeric form populated in the gas phase. Here, we have combined these three techniques to obtain insight into the structural properties of oligomers of Aβ1–40 and two variants with scrambled sequences. Gas-phase HDX-MS revealed a sequence-specific engagement of the side-chains of residues located at the N-terminal part of the peptide in a network of oligomer-stabilizing interactions. Oligomer-specific interactions were no longer observed in the case of the fully scrambled sequence. Also, the ability to form alternative structures, observed for WT Aβ peptide, was lost upon scrambling. Our data underscore a role for the N-terminal residues in shaping the equilibria of oligomeric forms. Although the peptide lacking the N-terminal 1–16 residues (p3 peptide) is thought to be benign, the role of the N-terminus has not been sufficiently characterized yet. We speculate that the interaction networks revealed here may be crucial for enabling structural transitions necessary to obtain mature parallel cross-β structures from smaller antiparallel oligomers. We provide a hypothetical molecular model of the trajectory that allows a gradual conversion from antiparallel to parallel oligomers without decomposition of oligomers. Oligomer-defining interactions involving the Aβ peptide N-terminus may be important in production of the neurotoxic forms and thus should not be neglected.
OriginalsprogEngelsk
Artikelnummere0201761
TidsskriftPLoS One
Vol/bind13
Udgave nummer8
Sider (fra-til)1-25
Antal sider25
ISSN1932-6203
DOI
StatusUdgivet - 6 aug. 2018

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