# Conformational and functional analysis of Apolipoprotein E

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $443,945

## Abstract

ABSTRACT
 The ε4-allele isoform of apolipoprotein E (ApoE4) plays a key-role in Alzheimer's disease and
cardiovascular pathologies. A large body of evidence support that conformations of the protein are instrumental
in its contribution to function and disease; yet, much remains unknown about the conformational ensemble of
full-length ApoE and its role in protein (dis)function, largely because of its elevated propensity for
aggregation/oligomerization and inherent flexibility.
 In our lab, we have overcome these complications by harnessing state-of-the-art single-molecule
fluorescence spectroscopy and, for the first time, we are able to access the structural ensemble of the
monomeric full-length ApoE4 (free in solution, embedded in oligomers, and bound to lipids). Our preliminary
data clearly indicate that ApoE4 adopts at least three distinct conformers – previously unidentified – that
coexist in equilibrium. These conformers are highly dynamic and malleable to oligomerization and lipid binding.
 These novel observations led us to hypothesize that single-point mutations and small molecules can
perturb the structural ensemble favoring/disfavoring specific “pathogenic” conformations, whereas interaction
with ligands (e.g. lipids) alters the equilibrium between the different conformers selecting for specific
conformations that are required for protein function. Our approach will allow us to determine the conformational
properties of ApoE, probe current structural models, and test our hypothesis. The specific aims are as follows:
1) determine the conformational changes and domain movements within the pathogenic ApoE4 and elucidate
how point mutations and small molecules modulate protein toxicity; 2) understand the mechanism of lipid
interactions, from synthetic lipid vesicles to physiological lipoproteins.
 A comprehensive description of the structural conformations and dynamics of ApoE in the presence
and absence of lipids will shed light on the molecular mechanism behind its role in health and disease, paving
the way to developing new therapeutic strategies.

## Key facts

- **NIH application ID:** 9922840
- **Project number:** 5R01AG062837-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Andrea Soranno
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $443,945
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9922840

## Citation

> US National Institutes of Health, RePORTER application 9922840, Conformational and functional analysis of Apolipoprotein E (5R01AG062837-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9922840. Licensed CC0.

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