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Prediction of Deleterious Non-synonymous SNPs of Human STK11 Gene by Combining Algorithms, Molecular Docking, and
Md Jahirul Islam1,2, Akib Mahmud Khan1, Md Rimon Parves2
1Division of Computer-Aided Drug Design, The Red-Green Research Centre, BICCB, 218 Elephant Road, Dhaka, 1205, Bangladesh.
Abstract:
Serine-threonine kinase11 (STK11) is a tumor suppressor gene which plays a key role in regulating cell growth and apoptosis. It is widely known as a multitasking kinase and engaged in cell polarity, cell cycle arrest, chromatin remodeling, energy metabolism, and Wnt signaling. The substitutions of single amino acids in highly conserved regions of the STK11 protein are associated with Peutz-Jeghers syndrome (PJS), which is an autosomal dominant inherited disorder. The abnormal function of the STK11 protein is still not well understood. In this study, we classified disease susceptible single nucleotide polymorphisms (SNPs) in STK11 by using different computational algorithms. We identified the deleterious nsSNPs, constructed mutant protein structures, and evaluated the impact of mutation by employing molecular docking and molecular dynamics analysis. Our results show that W239R and W308C variants are likely to be highly deleterious mutations found in the catalytic kinase domain, which may destabilize structure and disrupt the activation of the STK11 protein as well as reduce its catalytic efficiency. The W239R mutant is likely to have a greater impact on destabilizing the protein structure compared to the W308C mutant. In conclusion, these mutants can help to further realize the large pool of disease susceptibilities linked with catalytic kinase domain activation of STK11 and assist to develop an effective drug for associated diseases.
Insights
Computational analysis identified two key mutations, W239R and W308C, in the STK11 tumor suppressor gene. These STK11 variants likely destabilize the protein structure and impair its function, offering insights into Peutz-Jeghers syndrome.
Area of Science:
- Genetics and Molecular Biology
- Biochemistry
- Computational Biology
Background:
- Serine-threonine kinase 11 (STK11) is a crucial tumor suppressor gene regulating cell growth, apoptosis, polarity, and metabolism.
- STK11 mutations are linked to Peutz-Jeghers syndrome (PJS), an inherited disorder, but its abnormal function remains unclear.
Purpose of the Study:
- To computationally identify and analyze disease-susceptible single nucleotide polymorphisms (SNPs) in the STK11 gene.
- To evaluate the impact of specific STK11 mutations on protein structure and function using bioinformatics tools.
Main Methods:
- Utilized various computational algorithms to classify disease-susceptible SNPs in STK11.
- Employed molecular docking and molecular dynamics analysis to assess the effects of identified deleterious nsSNPs.
- Constructed mutant protein structures for W239R and W308C variants within the STK11 catalytic kinase domain.
Main Results:
- Identified W239R and W308C as highly deleterious mutations within the STK11 catalytic kinase domain.
- These mutations are predicted to destabilize the STK11 protein structure, disrupt its activation, and reduce catalytic efficiency.
- The W239R mutation is predicted to have a more significant impact on protein destabilization than W308C.
Conclusions:
- The identified W239R and W308C mutants provide valuable insights into STK11 kinase domain activation and associated disease susceptibilities.
- These findings can aid in developing targeted therapeutic strategies for diseases linked to STK11 dysfunction.
