Protein-protein interactions during cell-cycle control: The human oncoprotein gankyrin and GADD45gamma

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This project aims at biochemical and crystallographic studies of the human oncoprotein gankyrin and the human growth arrest and DNA damage-responsive protein GADD45γ. Gankyrin is the product of the first gene directly linked to hepatocellular carcinoma and was described to interact with the retinoblastoma protein (Rb), the cyclin-dependent protein kinases CDK4 and CDK6, the melanoma antigen A4 (MAGE-A4), the S6 ATPase of the 26S proteasome and the ubiquitin ligase Mdm2. The antiproliferative activity of GADD45γ is mediated by molecular interactions with the DNA polymerase δ processivity factor PCNA, the protein kinase MTK1 and the protein CRIF. In our planned biochemical and structural studies, we will focus on interactions of gankyrin with CDK4 and MAGE-A4, as well as GADD45γ with PCNA, MTK1 and CRIF. These interactions will be biochemically characterized, mapped to defined domains of the proteins and visualized by X-ray diffraction analysis of co-crystals. Small molecules available at the Screening Unit of the Max Delbrück Center and the Leibniz Institute for Molecular Pharmacology will be screened for their potential to inhibit selected proteinprotein interactions in which gankyrin or GADD45γ are engaged, partly based on a protocol for co-crystallisation-based ligand screening which we plan to develop.