%0 Journal Article
%T Mutations in Plasmodium falciparum Kelch13 (PfK13) dysregulates PI3K/AKT signalling pathway in artemisinin resistance.
%A Verma K
%A Singh Y
%A Kamaraj B
%A Sharma P
%A Schneider KA
%A Bharti PK
%J Indian J Med Microbiol
%V 51
%N 0
%D 2024 Aug 1
%M 39079616
%F 1.347
%R 10.1016/j.ijmmb.2024.100691
%X BACKGROUND: PfK13 protein mutations are associated with the emergence of artemisinin resistance in Plasmodium falciparum. PfK13 protein is essential for mediating ubiquitination and controlling the PI3K/AKT pathway. Mutant PfK13 variations can interfere with substrate binding, especially with PfPI3K, which raises PfPI3K levels.
METHODS: DUET, DynaMut2, mCSM, iStable 2.0, I-Mutant 2.0, and MuPro were utilized to study the protein stability and protein-substrate binding was studied using HADDOCK 2.4 docking algorithm between Wild-type and mutant PfK13 with the helical and catalytic domain of PfPI3K.
RESULTS: i-Stable server analysis predicted that seven, out of the nine mutations associated with artemisinin resistance (F446I, Y493H, R539T, I543T, P553L, R561H, C580Y) reduced the protein stability. HADDOCK scores of the catalytic domain underscores the significant impact of the reported mutations on the binding affinity of the PfK13 protein. Further validation through the MM_GBSA technique, the binding free energy (DDG) between the wild-type and the mutant PfK13 protein analysis revealed a loss of interactions resulting from mutations in PfK13.
CONCLUSIONS: The study finding suggest that mutations in the PfK13 cause destabilization in the protein structure and affects the binding of PfPI3K. Although the findings remain preliminary and require further validation, it provides the basis for further research considering the importance of the interaction of PfK13 and PfPI3K to overcome the impact of artemisinin resistance.