| While many skin cancers are readily treatable and yield a good prognosis, melanoma is the deadliest form of skin cancer, and this is due to its high propensity to metastasize and form additional tumors in tissue distant from the initial site of malignancy. The exact molecular mechanisms underlying the transition from localized nonmetastatic lesion to metastatic melanoma are poorly defined. The work presented here is focused on the characterization of the "Mediator of Rho-Dependent Invasion" (MRDI); a protein recently shown to be upregulated in late-stage melanoma and necessary for cell invasiveness associated with metastasis. I determined that MRDI is an enzyme required for methionine salvage, which catalyzes the isomerization of methylthioribose-1-phosphate to methylthioribulose-1-phosphate (i.e., an MTR-1P isomerase). However, it was also determined that this catalytic activity is not necessary to mediate invasive phenotypes indicating that MRDI has a secondary function in melanoma cells. To help identify the molecular mechanisms underlying its role in melanoma I determined the X-ray structure of MRDI. Although sequence similarity showed MRDI to be homologous to a protein family containing both isomerases and translation initiation factors, structural comparisons of MRDI with known MTR-1P isomerases places MRDI in the isomerase family and suggests that a role for MRDI in translation initiation is unlikely. Furthermore, I identified sequence motifs that allow unambiguous discrimination between these two protein families by sequence alignment. Several structural features in MRDI, which may mediate its role in melanoma, are discussed. |
