A Structural Model of the Extracellular Domain of the Oncogenic EGFR Variant Xmrk

The epidermal growth factor receptor (EGFR) variant Xmrk of the Mexican fish Xiphophorus is one of the first oncogenes described. Its overexpression in pigment cells of the skin occurs after certain repeated cross-breedings between the platyfish Xiphophorus maculatus and the swordtail Xiphophorus hellerii. Xmrk overexpression results in melanoma with a high malignant potential. The Xiphophorus melanoma model provides a valuable tool for the understanding of melanoma development in general. The xmrk gene is the duplicated version of the proto-oncogene egfr-b. Compared to this, it contains 14 nonsynonymous mutations. Two of these mutations lead to a permanent protein dimerization which results in constitutive signaling. For a better understanding of the structural conditions responsible for this effect, the authors modeled the extracellular domain of Egfr-b, based on the crystal structure of the closely related human EGFR, and introduced the mutations G336R or C555S. The resulting protein models show that in either mutation the formation of an intramolecular disulfide bridge is very likely prevented, leading to an intermolecular disulfide bridge between released cysteine residues. In the G336R model, the distance between the membrane-proximal domains from both chains is smaller than in the C555S model, confirming the previous observation than Egfr-b-G336R is more tumorigenic than Egfr-b-C555S in vivo.