Isoform- and Cell Type-specific Structure of Apolipoprotein E Lipoparticles As Revealed by a Novel Forster Resonance Energy Transfer Assay

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2017 Jul 8

PMID 28684412

Citations 16

Authors

Eleanna Kara

Jordan D Marks

Zhanyun Fan

Jacob A Klickstein

Allyson D Roe

Kelly A Krogh

Susanne Wegmann

Masato Maesako

Christina C Luo

Ravi Mylvaganam

Oksana Berezovska

Eloise Hudry

Bradley T Hyman

Affiliations

Soon will be listed here.

Abstract

Apolipoprotein E (apoE) has an important role in the pathogenesis of Alzheimer's disease with its three isoforms having distinct effects on disease risk. Here, we assessed the conformational differences between those isoforms using a novel flow cytometry-Forster resonance energy transfer (FRET) assay. We showed that the conformation of intracellular apoE within HEK cells and astrocytes adopts a directional pattern; in other words, E4 adopts the most closed conformation, E2 adopts the most open conformation, and E3 adopts an intermediate conformation. However, this pattern was not maintained upon secretion of apoE from astrocytes. Intermolecular interactions between apoE molecules were isoform-specific, indicating a great diversity in the structure of apoE lipoparticles. Finally, we showed that secreted E4 is the most lipidated isoform in astrocytes, suggesting that increased lipidation acts as a folding chaperone enabling E4 to adopt a closed conformation. In conclusion, this study gives insights into apoE biology and establishes a robust screening system to monitor apoE conformation.

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