RESEARCH ARTICLE
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, *
Article Information
Identifiers and Pagination:
Year: 2017Volume: 11
First Page: 84
Last Page: 93
Publisher ID: TOCMJ-11-84
DOI: 10.2174/1874192401711010084
Article History:
Received Date: 21/6/2017Revision Received Date: 30/6/2017
Acceptance Date: 08/7/2017
Electronic publication date: 14/09/2017
Collection year: 2017
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.
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.
