PT  - JOURNAL ARTICLE
AU  - Melissa D. Stuchell-Brereton
AU  - Maxwell I. Zimmerman
AU  - Justin J. Miller
AU  - Upasana L. Mallimadugula
AU  - J. Jeremias Incicco
AU  - Debjit Roy
AU  - Louis G. Smith
AU  - Berevan Baban
AU  - Gregory T. DeKoster
AU  - Carl Frieden
AU  - Gregory R. Bowman
AU  - Andrea Soranno
TI  - Apolipoprotein E4 has extensive conformational heterogeneity in lipid free and bound forms
AID  - 10.1101/2022.02.02.478828
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.02.02.478828
4099  - http://biorxiv.org/content/early/2022/02/04/2022.02.02.478828.short
4100  - http://biorxiv.org/content/early/2022/02/04/2022.02.02.478828.full
AB  - The ε4-allele variant of Apolipoprotein E (ApoE4) is the strongest genetic risk factor for Alzheimer’s disease, though it only differs from its neutral counterpart ApoE3 by a single amino acid substitution. While ApoE4 influences the formation of plaques and neurofibrillary tangles, the structural determinants of pathogenicity remain undetermined due to limited structural information. We apply a combination of single-molecule spectroscopy and molecular dynamics simulations to construct an atomically-detailed model of monomeric ApoE4 and probe the effect of lipid association. Our data reveal that ApoE4 is far more disordered than previously thought and retains significant conformational heterogeneity after binding lipids. In particular, the behavior of the hinge region and C-terminal domain of ApoE4 differs substantially from that proposed in previous models and provides a crucial foundation for understanding how ApoE4 differs from non-pathogenic and protective variants of the protein.Competing Interest StatementThe authors have declared no competing interest.