Conformational Plasticity of the MAGE-A3 Protein as a Therapeutic Strategy in Multiple Myeloma

Type I MAGE proteins interact with the RING domain protein Kap1 through their conserved MAGE Homology Domains (MHD) to form E3 ubiquitin (Ub) ligases, which ubiquitinylate p53 targeting it for proteasomal degradation. RNAi experiments demonstrated that MAGE-A3 inhibits p53-dependent and independent mechanisms of apoptosis and confers resistance to chemotherapy-induced apoptosis in human myeloma cell lines. Since MAGE expression correlates with progression of multiple myeloma (MM), preventing the interaction with Kap1 is a promising therapeutic intervention against MM.