Structural and Molecular Interaction Studies on Familial Hypercholesterolemia Causative PCSK9 Functional Domain Mutation
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Structural and Molecular Interaction Studies on Familial Hypercholesterolemia Causative PCSK9 Functional Domain Mutations Reveals Binding Affinity Alterations with LDLR Zuhier Ahmed Awan1 · Rawabi Bahattab2,3 · Hussam Ibrahim Kutbi4 · Ahmad Omar Jamal Noor4 · Marzog S. Al‑Nasser5 · Noor Ahmad Shaik2,3 · Babajan Banaganapalli2,3 Accepted: 28 September 2020 © Springer Nature B.V. 2020
Abstract Familial hypercholesterolemia (FH) is a metabolic disease caused by the inherited pathogenic mutations in PCSK9 gene. This study has evaluated the potential of diverse computational methods in predicting the PCSK9 clinical variants and also studied the impacts of mutation on protein phenotype and function. Our findings show the superior prediction ability of FATHMM over CADD, M-CAP, SIFT and Polyphen methods, in screening PCSK9 missense mutations causative to FH. Computational 3D mapping of PCSK9 variants located in prodomain (K83T), catalytic domain (D204N) and c-terminal domains (K494E) revealed mutant residue induced disturbances in the tertiary structure of protein. These variants are also predicted to impair the free energy dynamics, hence stability of PCKS9 as per the consensual predictions made by protein structure-based prediction algorithms like SAAFEC and MAESTRO. Molecular docking assay by PIZMA algorithm showed the increased binding affinity between PCSK9 variants and LDLR molecules. Furthermore, the results from PDBsum method have also suggested changes in interfacing residues, interface area, salt bridge and ionic bond interactions confirming the findings from docking analysis. The PCSK9 functional domain mutations could increase its binding affinity with LDLR, eventually promoting LDLR degradation in lysosomes and elevate circulating cholesterol levels in body. This study supports the application of comprehensive computational assessment of FH causative PCSK9 mutations before undertaking labor intensive functional biology investigations. Keywords PCKS9 · Familial hypercholesterolemia · Protein–protein interaction · Protein structural network · Molecular docking
Introduction
* Babajan Banaganapalli [email protected] 1
Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
2
Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
3
Princess Al‑Jawhara Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia
4
Department of Pharmacy Practice, Faculty of Pharmacy, King Abdulaiziz University, Jeddah, Saudi Arabia
5
Department of Clinical Pharmacology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
Familial hypercholesterolemia (FH) is an inherited metabolic disease characterized by an elevated concentration of blood low-density lipoprotein (LDL)-cholesterol (C) and its reduced catabolism (Bouhairie and Goldberg 2015). If untreated, the high LDL-C levels in blood leads to the accumulation of cholesterol in tissues which conseq
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