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Copyright (c) 2025 Mohammed Tarique, Ayyub Ali Patel, Ayaz Khurram Mallick, Rania A. Hussien, Tarek Mahmoud Mirdad, Zia-Ul-Sabah, Rasha Mirdad, Imad Mohammad Alghawanmeh, Mohamed Babiker Abdelrouf Awadelkarim, Mohammad Azhar Kamal, Hani Alothaid
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
The undersigned hereby assign all rights, included but not limited to copyright, for this manuscript to CMB Association upon its submission for consideration to publication on Cellular and Molecular Biology. The rights assigned include, but are not limited to, the sole and exclusive rights to license, sell, subsequently assign, derive, distribute, display and reproduce this manuscript, in whole or in part, in any format, electronic or otherwise, including those in existence at the time this agreement was signed. The authors hereby warrant that they have not granted or assigned, and shall not grant or assign, the aforementioned rights to any other person, firm, organization, or other entity. All rights are automatically restored to authors if this manuscript is not accepted for publication.Structural dynamics of PCSK9 loss-of-function variants: implications for LDL cholesterol regulation and cardiovascular risk
Corresponding Author(s) : Mohammad Azhar Kamal
Cellular and Molecular Biology,
Vol. 71 No. 12: Issue 12
Abstract
Cardiovascular disease (CVD) is a leading global cause of mortality, and understanding its underlying mechanisms is crucial for developing effective interventions. The liver-derived protein PCSK9 (proprotein convertase subtilisin/kexin-type-9) plays a vital role in regulating lipoprotein metabolism by binding to the low-density lipoprotein receptor (LDLR) and promoting its lysosomal degradation, ultimately reducing low-density lipoprotein (LDL) clearance. Loss-of-function (LOF) variants in PCSK9 are associated with decreased LDL cholesterol (LDL-C) levels, suggesting that these variants may contribute to a lower risk of cardiovascular events. Our computational analysis of PCSK9 LOF variants revealed significant alterations in stability, flexibility, and free energy compared to the native protein. Protein-protein docking studies of both wildtype and mutant PCSK9 with LDLR demonstrated variations in binding energy and interacting residues. Notably, while the binding cavity remained the same as that of the wildtype, all variants exhibited distinct binding interactions. Molecular dynamics simulations further highlighted increased flexibility and solvent exposure in the mutant protein complexes. These findings indicate that LOF variants in PCSK9 induce substantial structural changes, leading to a decreased affinity for LDLR binding.
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