Pathogenic single nucleotide polymorphisms in RhoA gene: Insights into structural and functional impacts on RhoA-PLD1...

Area of Science:

• Molecular biology and genetics
• Computational biology and bioinformatics
• Structural biology

Background:

• Molecular switches like RhoA (Ras homolog gene family member A) are critical for signal transduction.
• Aberrant RhoA function, often due to genetic variations, is linked to various diseases.
• Single nucleotide polymorphisms (SNPs) in RhoA can alter protein structure and function, influencing pathogenicity.

Purpose of the Study:

• To computationally screen for deleterious nonsynonymous SNPs (nsSNPs) in the RhoA gene.
• To investigate the structural and functional impacts of identified deleterious RhoA mutations.
• To explore the potential role of these mutations in RhoA-GDP-PLD1 complex interactions and disease.

Main Methods:

• Screening of 207 RhoA nsSNPs using seven distinct computational tools.
• Identification of common deleterious SNPs located in conserved regions and GTP-binding motifs.
• Structural analysis of selected RhoA mutations and 250 ns molecular dynamics (MD) simulations of RhoA-GDP-PLD1 complexes.

Main Results:

• Eight common deleterious SNPs were identified, with five (V9G, G17E, E40K, A61T, F171L) in conserved regions.
• Mutations E40K and A61T potentially affect GTP/GDP binding due to their location in key motifs.
• MD simulations revealed structural instability and altered interactions for G17E and I86N mutations in the RhoA-GDP-PLD1 complex.

Conclusions:

• Deleterious RhoA SNPs, particularly G17E and I86N, can significantly impact protein structure and interactions.
• These mutations may affect RhoA's interaction with PLD1, a key regulator in thrombosis and cancer.
• Further in vitro and in vivo studies are warranted to validate these findings as potential biomarkers and therapeutic targets.