Both BC-box motifs of adenovirus protein E4orf6 are required to efficiently assemble an E3 ligase complex that degrades p53.
Small DNA tumor viruses typically encode proteins that either inactivate or degrade p53. Human adenoviruses encode products, including E4orf6 and E1B55K, that do both. Each independently binds to p53 and inhibits its ability to activate gene expression; however, in combination they induce p53 degradation by the ubiquitin pathway. We have shown previously that p53 degradation relies on interactions of E4orf6 with the cellular proteins Cul5, Rbx1, and elongins B and C to form an E3 ligase similar to the SCF and VBC complexes. Here we show that, like other elongin BC-interacting proteins, including elongin A, von Hippel-Lindau protein, and Muf1, the interaction of E4orf6 is mediated by the BC-box motif; however, E4orf6 uniquely utilizes two BC-box motifs for degradation of p53 and another target, Mre11. In addition, our data suggest that the interaction of E1B55K with E4orf6 depends on the ability of E4orf6 to form the E3 ligase complex and that such complex formation may be required for all E4orf6-E1B55K functions.
McGill University, McIntyre Medical Building, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6.
Paola
P
Blanchette
Chi Ying
CY
Cheng
Qin
Q
Yan
Gary
G
Ketner
David A
DA
Ornelles
Thomas
T
Dobner
Ronald C
RC
Conaway
Joan Weliky
JW
Conaway
Philip E
PE
Branton
D017501:Adenovirus E1B Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017504:Adenovirus E4 Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000260:Adenoviruses, Human / Q000378:metabolism*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D000075065:Elongin; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000076228:MRE11 Homologue Protein; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000378:metabolism*
D017501:Adenovirus E1B Proteins; D017504:Adenovirus E4 Proteins; D044842:Cullin Proteins; D004268:DNA-Binding Proteins; C000616397:ELOA protein, human; D000075065:Elongin; C121766:MRE11 protein, human; D046912:Multiprotein Complexes; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D000076228:MRE11 Homologue Protein