COMPUTATIONAL ANALYSIS OF KIT-SCF INTERACTIONS

Background:

Stem cell factor (SCF) is a cytokine that mediates diverse cellular responses by binding and activating the receptor tyrosine kinase KIT. SCF and KIT are required for a normal development of various cells, including hematopoietic cells and melanocytes, while mutations in KIT were found in different types of human cancers.

Purpose and methods:

To predict and explain the effect of point mutations in SCF and KIT, we used computational methods to analyze the SCF-KIT complex. Calculations of electrostatic energy contributions, per-residue surface burial among others helped us to predict the contributions of particular amino acids to binding affinity and suggest putative mechanisms for the effects of mutagenesis.

Results:
Our analysis predicts accurately the impact of replacing particular amino acids and the influence on receptor dimerization or ligand binding, correlating well with experimental results.

Conclusions:
Our approach enables to predict and explain the effect of mutagenesis on KIT receptor dimerization or SCF binding. Our results can direct the redesign of SCF and KIT and enable similar analysis of other tyrosine kinase receptors and their ligands.