Identification and structural characterization of deleterious non-synonymous single nucleotide polymorphisms in the...

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Biology

Background:

• The SCF (Skp, Cullin, F-box) ubiquitin-protein ligase complex regulates protein degradation.
• S-phase kinase 2 (SKP2) is a key F-box protein involved in cell cycle regulation and tumor suppression.
• The impact of SKP2 non-synonymous single nucleotide polymorphisms (nsSNPs) on its function is largely uncharacterized.

Purpose of the Study:

• To computationally investigate the structural and functional consequences of nsSNPs in SKP2.
• To identify specific nsSNPs that may negatively impact SKP2 stability and function.
• To provide a basis for further experimental validation and drug development targeting SKP2.

Main Methods:

• Utilized multiple computational tools (SIFT, PolyPhen-2, PredictSNP, I-Mutant 2.0, ConSurf) to predict damaging nsSNPs.
• Performed 3D model building and molecular dynamics simulations for selected mutations.
• Analyzed the impact of mutations on protein stability, flexibility, and structural dynamics.

Main Results:

• Identified 5 deleterious nsSNPs out of 172 analyzed.
• Three nsSNPs were predicted to decrease protein stability.
• P101L (rs761253702) and Y346C (rs755010517) were identified as highly conserved and functionally disruptive mutations.
• Molecular dynamics simulations showed P101L and Y346C mutations increase protein flexibility and alter structural dynamics.

Conclusions:

• The identified nsSNPs, particularly P101L and Y346C, significantly alter SKP2 protein structure and dynamics.
• These mutations occur in functionally important regions of SKP2.
• The findings support further wet-lab investigation of these nsSNPs and their role in cancer.
• Computational insights can guide future population studies and structure-based drug design targeting SKP2.