The structure of Apolipoprotein E isoforms and their role in Alzheimer's disease Public Deposited

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  • March 20, 2019
Creator
  • Williams, Benfeard
    • Affiliation: School of Medicine, Department of Biochemistry and Biophysics
Abstract
  • Alzheimer’s disease (AD) is a chronic, incurable neurodegenerative disorder. AD is the most common form of dementia. The strongest genetic risk factor for AD is the expression of the E4 isoform of Apolipoprotein E (ApoE4), found in ~15% of the population. The other two common variants of this protein, namely ApoE2 and ApoE3, are respectively protective and neutral isoforms in regards to the development of AD. The three ApoE variants are strikingly similar in sequence, differing only at two locations. However, biophysical studies reveal that while functionally comparable to the other variants, ApoE4 is less thermally stable and shows a misfolded intermediate state, which has been associated with the onset of AD. Despite the strong connection to AD and extensive research in lipid metabolism, the ApoE4 structural features responsible for its pathogenic role in AD remain unresolved. In this work, we explore the unique conformational landscape of ApoE isoforms to identify specific structural features responsible for AD onset. We perform a series of molecular dynamics simulations for all three ApoE isoforms, and we find that ApoE4 has access to a unique folding intermediate conformation with inter-domain interactions not seen in ApoE2 or ApoE3. We generate a structural model of an ApoE4-specific misfolded state to predict mutations that can affect the stability of key contacts in this specific conformation. In addition to identifying interacting residues in the misfolded intermediate state, we create models with C-terminal truncations to narrow in on the most vital inter-domain contacts. To determine the inherent isoform differences, we study residue communication networks using dynamic cross- correlations to show that even in the native conformation, ApoE4 exhibits unique dynamic properties that ultimately lead to its distinctive conformational landscape. Our findings suggest that the underlying role of ApoE4 in the development of AD can be linked to its isoform-specific structural and conformational dynamics.
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  • In Copyright
Advisor
  • Zhang, Qi
  • Major, Ben
  • Campbell, Sharon
  • Cohen, Todd
  • Dokholyan, Nikolay
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2017
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