Influence of PRKCE non-synonymous variants on protein dynamics and functionality

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• Protein kinase C epsilon (PKCε), a member of the novel protein kinase C (nPKC) family and AGC kinase superfamily, is implicated in neurological disorders, metabolic diseases, and cancers.
• No prior research has investigated genetic variations affecting PKCε folding and function.

Purpose of the Study:

• To identify mutational hotspots and disease-causing non-synonymous single nucleotide polymorphisms (nsSNPs) in PKCε.
• To investigate the impact of nsSNPs on PKCε protein dynamics and function.
• To predict post-translational modification (PTM) sites in PKCε.

Main Methods:

• Utilized twenty-nine in silico tools to analyze nsSNP deleteriousness, disease association, and impact on protein dynamics.
• Predicted PTM sites within the PKCε protein.

Main Results:

• Identified nsSNP clustering in the PKCε hinge region and C-terminal tail, with most pathogenic variants located in the kinase domain.
• Observed that regulatory domain variants affect molecular interactions, while kinase domain variants impact phosphorylation and protein-protein interactions.
• Localized most PTM sites to the hinge region.

Conclusions:

• PKCε nsSNPs are associated with oncogenicity, and their dysregulation contributes to poor survival rates.
• Understanding the structural impact of nsSNPs is crucial for linking genetic variations to protein phenotypes.
• This research provides foundational knowledge for developing diagnostic and therapeutic strategies for PKCε-related diseases.