Native Mass Spectrometry, Ion Mobility, Electron-Capture Dissociation, and Modeling Provide Structural Information for Gas-Phase Apolipoprotein E Oligomers

Hanliu Wang, Joseph Eschweiler, Weidong Cui, Hao Zhang, Carl Frieden, Brandon T. Ruotolo, Michael L. Gross

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Apolipoprotein E (apoE) is an essential protein in lipid and cholesterol metabolism. Although the three common isoforms in humans differ only at two sites, their consequences in Alzheimer’s disease (AD) are dramatically different: only the ε4 allele is a major genetic risk factor for late-onset Alzheimer’s disease. The isoforms exist as a mixture of oligomers, primarily tetramer, at low μM concentrations in a lipid-free environment. This self-association is involved in equilibrium with the lipid-free state, and the oligomerization interface overlaps with the lipid-binding region. Elucidation of apoE wild-type (WT) structures at an oligomeric state, however, has not yet been achieved. To address this need, we used native electrospray ionization and mass spectrometry (native MS) coupled with ion mobility (IM) to examine the monomer and tetramer of the three WT isoforms. Although collision-induced unfolding (CIU) cannot distinguish the WT isoforms, the monomeric mutant (MM) of apoE3 shows higher stability when submitted to CIU than the WT monomer. From ion-mobility measurements, we obtained the collision cross section and built a coarse-grained model for the tetramer. Application of electron-capture dissociation (ECD) to the tetramer causes unfolding starting from the C-terminal domain, in good agreement with solution denaturation data, and provides additional support for the C4 symmetry structure of the tetramer. [Figure not available: see fulltext.]

Original languageEnglish
Pages (from-to)876-885
Number of pages10
JournalJournal of the American Society for Mass Spectrometry
Volume30
Issue number5
DOIs
StatePublished - May 16 2019

Keywords

  • Alzheimer’s disease
  • Coarse-grained modeling
  • Collision-induced unfolding
  • Electron capture dissociation
  • Native mass spectrometry
  • Structure of Apolipoprotein E (ApoE) tetramer

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