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In Silico Insights into Protein-protein Interaction Disruptive Mutations in the PCSK9-LDLR complex

William R Martin1, Felice C Lightstone2, Feixiong Cheng1,3,4

  • 1Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

International Journal of Molecular Sciences
|February 29, 2020
PubMed

Insights

Gain-of-function mutations in PCSK9 enhance its binding to the LDL receptor, disrupting LDL cholesterol uptake. These mutations alter protein interactions, potentially implicating the PCSK9 prodomain as a therapeutic target.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Computational Biology

Background:

  • Gain-of-function mutations in PCSK9 (proprotein convertase subtilisin/kexin type 9) increase plasma LDL cholesterol by reducing LDL uptake.
  • The precise mechanism by which these PCSK9 mutations impair LDL receptor function remains unclear.

Purpose of the Study:

  • To investigate the protein-protein interaction (PPI) disruptive effects of PCSK9 gain-of-function mutations on the PCSK9-LDL receptor complex.
  • To elucidate the molecular mechanisms underlying reduced LDL reuptake caused by PCSK9 mutations.

Main Methods:

  • Molecular dynamics simulations.
  • MM/PBSA binding affinity calculations.
  • Residue interaction network analysis.

Main Results:

  • Ser127Arg and Asp374Tyr mutations significantly enhanced PCSK9 binding affinity to the LDL receptor compared to wild-type.
  • These mutations alter binding modes at critical interfaces: PCSK9 catalytic domain with LDL receptor EGF(A) domain (Asp374Tyr) and PCSK9 prodomain with LDL receptor β-propeller (Ser127Arg).
  • The altered interactions sterically inhibit the LDL receptor from adopting its closed conformation.

Conclusions:

  • Gain-of-function PCSK9 mutations disrupt LDL receptor function through specific PPI alterations.
  • The PCSK9 prodomain emerges as a potential target for developing small molecule inhibitors to modulate PCSK9-LDL receptor interactions.
Keywords:
LDLRMM/PBSAMolecular DynamicsPCSK9PPI disruptive mutationprotein–protein interaction (PPI)residue interaction network

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