Department of Biology, College of Sciences, Shiraz University
Microtubule Affinity-Regulating Kinase 2 (MARK2) protein has a substantial role in regulation of vital cellular processes like induction of polarity, regulation of cell junctions, cytoskeleton structure and cell differentiation. The abnormal function of this protein has been associated with a number of pathological conditions like Alzheimer disease, autism, several carcinomas and development of virulent effects of Helicobacter pylori. Here we tried to verify the structural changes induced in MARK2 by T208E activating mutation using molecular modeling and molecular dynamics simulation. Our results show that the enzyme structure shifts toward the active state due to T208E mutation, but this process is not a uniform change in all through the expected regions. Within the N-lobe of the protein, those functional regions having little or no interaction with the UBA domain, like N-half of b2, b4 strands and aC-helix, go through activating motions and those having close interactions with UBA domain like C-half of b1, b3 and b5 strands are comparatively held in-place and don’t accompany. Within the C-lobe, only activation segment has noticeable displacements. Free energy calculations also indicate higher affinity of UBA domain for protein N-lobe in mutant structure (∆∆G = -9 kJ/mol) which is suggestive of a more intimate interaction between the UBA domain and protein N-lobe in mutant structure.
MARKII, Kinase protein regulation, UBA domain, Auto-inhibition, Structural dynamics
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