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Characterization of the N- and C-terminal domain interface of the three main apoE isoforms: A combined quantitative cross-linking mass spectrometry and molecular modeling study

par Mohammadi, Azadeh ;Deroo, Stéphanie ;Leitner, Alexander A. L.;Stengel, Florian;Krammer, Eva-Maria ;Aebersold, Rudolf;Prévost, Martine ;Raussens, Vincent
Référence Biochimica et biophysica acta (G). General subjects, 1869, 4, page (130768)
Publication A Paraître, 2025-04-30

Article révisé par les pairs

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Résumé :

Apolipoprotein E (apoE) polymorphism is associated with different pathologies such as atherosclerosis and Alzheimer's disease. Knowledge of the three-dimensional structure of apoE and isoform-specific structural differences are prerequisites for the rational design of small molecule structure modulators that correct the detrimental effects of pathological isoforms. In this study, cross-linking mass spectrometry (XL-MS) targeting Asp, Glu and Lys residues was used to explore the intramolecular interactions in the E2, E3 and E4 isoforms of apoE. The resulting quantitative XL-MS data combined with molecular modeling revealed isoform-specific characteristics of the N- and C-terminal domain interfaces as well as the isoform-dependent dynamic equilibrium of these interfaces. Finally, the data identified a network of salt bridges formed by R61-R112-E109 residues in the N-terminal helical bundle as a modulator of the interaction with the C-terminal domain making this network a potential drug target.