Interpreting the Mechanism of APOE (p.Leu167del) Mutation in the Incidence of Familial Hypercholesterolemia; An In-silico Approach



Omran Mohammed Rashidi1, #, Fatima Amanullah H.Nazar2, #, Mohamed Nabil Alama3, Zuhier Ahmed Awan1, *
1 Department of Clinical Biochemistry. Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
2 Department of Biology, Genomic and Biotechnology Section. Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
3 Adult interventional cardiology, Cardiology unit, King Abdulaziz University Hospital (KAUH), Jeddah, Saudi Arabia


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© 2017 Rashidi et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Division of Clinical Biochemistry, King Abdulaziz University, Abdullah Sulayman, Jeddah 22254, Saudi Arabia, Tel: +966-12-640-1000# 73717 / 22123; Fax: 640-8451; E-mails: zawan@kau.edu.sa; zuhier.awan@gmail.com

# Equal contribution and Shared first authorship


Abstract

Background:

Apolipoprotein E (APOE) gene is a ligand protein in humans which mediates the metabolism of cholesterol by binding to the low-density lipoprotein receptor (LDLR). P.Leu167del mutation in APOE gene was recently connected with Familial Hypercholesterolemia, a condition associated with premature cardiovascular disease. The consequences of this mutation on the protein structure and its receptor binding capacity remain largely unknown.

Objective:

The current study aims to further decipher the underlying mechanism of this mutation using advanced software-based algorithms. The consequences of disrupting the leucine zipper by this mutation was studied at the structural and functional level of the APOE protein.

Methods:

3D protein modeling for both APOE and LDLR (wild types), along with APOE (p.Leu167del) mutant type were generated using homology modeling template-based alignment. Structural deviation analysis was performed to evaluate the spatial orientation and the stability of the mutant APOE structure. Molecular docking analysis simulating APOE-LDLR protein interaction was carried out, in order to evaluate the impact of the mutation on the binding affinity.

Result:

Structural deviation analysis for APOE mutated model showed low degree of deviance scoring root-mean-square deviation, (RMSD) = 0.322 Å. Whereas Docking simulation revealed an enhanced molecular interaction towards the LDLR with an estimation of +171.03 kJ/mol difference in binding free energy.

Conclusion:

This in-silico study suggests that p.Leu167del is causing the protein APOE to associate strongly with its receptor, LDLR. This gain-of-function is likely hindering the ability of LDLR to be effectively recycled back to the surface of the hepatocytes to clear cholesterol from the circulation therefore leading to FH.



Keywords: Apolipoprotein E (APOE), P. Leu167del, Familial Hypercholesterolemia (FH), Homology modeling, Structural deviation, Molecular Docking Simulation.