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

Martin, William R.; Lightstone, Felice C.; Cheng, Feixiong

doi:10.3390/ijms21051550

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

Journal Article · Tue Feb 25 00:00:00 EST 2020 · International Journal of Molecular Sciences (Online)

DOI:https://doi.org/10.3390/ijms21051550· OSTI ID:1628389

Martin, William R. ^[1]; Lightstone, Felice C. ^[2]; ^[3]

Cleveland Clinic, Cleveland, OH (United States). Genomic Medicine Institute, Lerner Research Institute; DOE/OSTI
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Biosciences and Biotechnology Division, Physical and Life Sciences Directorate
Cleveland Clinic, Cleveland, OH (United States). Genomic Medicine Institute, Lerner Research Institute; Case Western Reserve University, Cleveland, OH (United States). Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine; Case Western Reserve University, Cleveland, OH (United States). Case Comprehensive Cancer Center

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 Accepted Manuscript (DOE)

Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE National Nuclear Security Administration (NNSA)

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 1628389

Alternate ID(s):: OSTI ID: 1877977

Report Number(s):: LLNL-JRNL-804830; PII: ijms21051550

Journal Information:: International Journal of Molecular Sciences (Online), Journal Name: International Journal of Molecular Sciences (Online) Journal Issue: 5 Vol. 21; ISSN IJMCFK; ISSN 1422-0067

Publisher:: MDPICopyright Statement

Country of Publication:: United States

Language:: English

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