Interpreting the Mechanism of APOE (p.Leu167del) Mutation in the Incidence of Familial Hypercholesterolemia; An In-silico Approach.
PMID 29204218 | PMCID PMC5688386 | DOI 10.2174/1874192401711010084 · The open cardiovascular medicine journal · 2017
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.
Validated evidence
| Type | Entity | Source evidence | Confidence | Extractor |
|---|---|---|---|---|
| gene | APOE | “Interpreting the Mechanism of APOE (p.Leu167del) Mutation in the Incidence of Familial Hypercholesterolemia; An In-silico Approach.” | 0.98 | hgnc_dict_v1 |
| gene | LDLR | “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).” | 0.98 | hgnc_dict_v1 |
| phenotype | familial hypercholesterolemia | “Interpreting the Mechanism of APOE (p.Leu167del) Mutation in the Incidence of Familial Hypercholesterolemia; An In-silico Approach.” | 0.98 | phenotype_alias_lexicon_v2 |