Impact of glioblastoma multiforme associated mutations on the structure and function of MAP/microtubule affinity regulating kinase 4

MAP/Microtubule affinity regulating kinase 4 (MARK4) plays an important role in the regulation of microtubule dynamics by phosphorylation of tau protein. A higher expression of MARK4 is observed in the glioblastoma multiforme (GBM) cell lines. We identified eight synonymous and non-synonymous mutations in the MARK4 gene related to GBM in The Cancer Genome Atlas (TCGA) consortium. Out of these, three non-synonymous mutations were found in the catalytic domain of the protein (Lys231Asn, Tyr247His and Arg265Gln), were selected to see the possible deleterious effects on the structure and function using the cutting-edge in-silico tools. In addition, molecular dynamics simulation, principal component analysis, dynamic cross correlation matrix analysis and correlation network analysis were performed to gain insights into the conformation of the MARK4 and its mutants. We found that, Tyr247His shows a maximum deleterious impact, reflected from structural deviation in comparison to Lys231Asn and Arg265Gln. In conclusion, Tyr247His mutant of MARK4 has relatively higher chances of affecting the structure and function of the protein thus leading to abnormal MARK4 activity which is associated to GBM.Communicated by Ramaswamy H. Sarma.