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Article

In Silico Insights into Protein–Protein Interaction Disruptive Mutations in the PCSK9-LDLR Complex

1
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
2
Biosciences and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, CA 94550, USA
3
Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA
4
Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(5), 1550; https://doi.org/10.3390/ijms21051550
Received: 13 January 2020 / Revised: 10 February 2020 / Accepted: 21 February 2020 / Published: 25 February 2020
(This article belongs to the Collection Feature Papers in Molecular Biophysics)
Gain-of-function mutations in PCSK9 (proprotein convertase subtilisin/kexin type 9) lead to reduced uptake of LDL (low density lipoprotein) cholesterol and, therefore, increased plasma LDL levels. However, the mechanism by which these mutants reduce LDL reuptake is not fully understood. Here, we have used molecular dynamics simulations, MM/PBSA (Molecular Mechanics/Poisson–Boltzmann Surface Area) binding affinity calculations, and residue interaction networks, to investigate the protein–protein interaction (PPI) disruptive effects of two of PCSK9′s gain-of-function mutations, Ser127Arg and Asp374Tyr on the PCSK9 and LDL receptor complex. In addition to these PPI disruptive mutants, a third, non-interface mutation (Arg496Trp) is included as a positive control. Our results indicate that Ser127Arg and Asp374Tyr confer significantly improved binding affinity, as well as different binding modes, when compared to the wild-type. These PPI disruptive mutations lie between the EGF(A) (epidermal growth factor precursor homology domain A) of the LDL receptor and the catalytic domain of PCSK9 (Asp374Tyr) and between the prodomain of PCSK9 and the β-propeller of the LDL receptor (Ser127Arg). The interactions involved in these two interfaces result in an LDL receptor that is sterically inhibited from entering its closed conformation. This could potentially implicate the prodomain as a target for small molecule inhibitors. View Full-Text
Keywords: PCSK9; LDLR; Molecular Dynamics; MM/PBSA; protein–protein interaction (PPI); PPI disruptive mutation; residue interaction network PCSK9; LDLR; Molecular Dynamics; MM/PBSA; protein–protein interaction (PPI); PPI disruptive mutation; residue interaction network
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MDPI and ACS Style

Martin, W.R.; Lightstone, F.C.; Cheng, F. In Silico Insights into Protein–Protein Interaction Disruptive Mutations in the PCSK9-LDLR Complex. Int. J. Mol. Sci. 2020, 21, 1550. https://doi.org/10.3390/ijms21051550

AMA Style

Martin WR, Lightstone FC, Cheng F. In Silico Insights into Protein–Protein Interaction Disruptive Mutations in the PCSK9-LDLR Complex. International Journal of Molecular Sciences. 2020; 21(5):1550. https://doi.org/10.3390/ijms21051550

Chicago/Turabian Style

Martin, William R.; Lightstone, Felice C.; Cheng, Feixiong. 2020. "In Silico Insights into Protein–Protein Interaction Disruptive Mutations in the PCSK9-LDLR Complex" Int. J. Mol. Sci. 21, no. 5: 1550. https://doi.org/10.3390/ijms21051550

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