MAGE-RING protein complexes comprise a family of E3 ubiquitin ligases.
The melanoma antigen (MAGE) family consists of more than 60 genes, many of which are cancer-testis antigens that are highly expressed in cancer and play a critical role in tumorigenesis. However, the biochemical and cellular functions of this enigmatic family of proteins have remained elusive. Here, we identify really interesting new gene (RING) domain proteins as binding partners for MAGE family proteins. Multiple MAGE family proteins bind E3 RING ubiquitin ligases with specificity. The crystal structure of one of these MAGE-RING complexes, MAGE-G1-NSE1, reveals structural insights into MAGE family proteins and their interaction with E3 RING ubiquitin ligases. Biochemical and cellular assays demonstrate that MAGE proteins enhance the ubiquitin ligase activity of RING domain proteins. For example, MAGE-C2-TRIM28 is shown to target p53 for degradation in a proteasome-dependent manner, consistent with its tumorigenic functions. These findings define a biochemical and cellular function for the MAGE protein family.
Doyle
Jennifer M
JM
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9038, USA.
Gao
Jinlan
J
Wang
Jiawei
J
Yang
Maojun
M
Potts
Patrick Ryan
PR
D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D055162:Biocatalysis; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D018360:Crystallography, X-Ray; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D058950:Melanoma-Specific Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D020836:Protein Structure, Quaternary; D054829:RING Finger Domains; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000076183:Tripartite Motif-Containing Protein 28; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D000951:Antigens, Neoplasm; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C405429:MAGEC2 protein, human; C420909:Mage-a2 antigen; D058950:Melanoma-Specific Antigens; C533270:NSMCE1 protein, human; C469927:NSMCE3 protein, human; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C484733:LNX1 protein, human; C484661:PJA1 protein, human; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28; D044767:Ubiquitin-Protein Ligases