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Mutation research. Fundamental and molecular mechanisms of mutagenesis v.808, 2018년, pp.28 - 38   SCI SCIE
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A change in structural integrity of c-Kit mutant D816V causes constitutive signaling

Raghav, Pawan Kumar (Corresponding author. ) ; Singh, Ajay Kumar ; Gangenahalli, Gurudutta ;
  • 초록  

    Abstract Several signaling pathways, ligands, and genes that regulate proliferative and self-renewal properties of the Hematopoietic Stem Cells (HSCs) have been studied meticulously. One of the signaling pathways that play a crucial role in the process of hematopoiesis is the Stem Cell Factor (SCF) mediated c-Kit pathway. The c-Kit is a Receptor Tyrosine Kinase (RTK), which is expressed in the cells including HSCs. It undergoes dimerization upon binding with its cognate ligand SCF. As a result, phosphorylation of the Juxtamembrane (JM) domain of c-Kit takes place at Tyr568 and Tyr570 residues. These phosphorylated residues become the docking sites for protein tyrosine phosphatases (PTPs) namely SHP-1 and SHP-2, which in turn cause dephosphorylation and negative regulation of the downstream signaling responsible for the cell proliferation. Interestingly, it has been reported that the mutation of c-Kit at D816V makes it independent of SCF stimulation and SHP-1/SHP-2 inhibition, thereby, causing its constitutive activation. The present study was commenced to elucidate the structural behavior of this mutation in the JM and A-loop region of c-Kit using Molecular Dynamics (MD) simulations of the wild-type and mutant c-Kit in unphosphorylated and phosphorylated states. The energy difference computed between the wild type and mutant (D816V) c-Kit, and protein–protein docking and complex analysis revealed the impact of this single residue mutation on the integrity dynamics of c-Kit that makes it independent of SHP-1/SHP-2 negative regulation. Highlights Elucidation of the molecular mechanism underlying the independence and self-reliance of c-Kit mutation (D816V). Presence of additional intramolecular hydrogen bonds in D816V c-Kit mutant. Integrity dynamics of the Mutant D816V structure affects the binding site of the negative regulators. Graphical abstract [DISPLAY OMISSION]


  • 주제어

    c-Kit .   SCF .   Proliferation .   PTPs.  

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