Identification of the Adenovirus E4orf4 Protein Binding Site on the B55α and Cdc55 Regulatory Subunits of PP2A: Implications for PP2A Function, Tumor Cell Killing and Viral Replication

PLoS Pathogens

Michael Kucharski¹  Marie-Joëlle Miron¹  Woosuk Steve Hur¹  Philip E. Branton¹  Albert M. Berghuis¹  Melissa Z. Mui¹  Paola Blanchette¹ 

[1] Department of Biochemistry, McGill University, Montreal, Quebec, Canada

关键词: Co-immunoprecipitation;    Toxicity;    Adenoviruses;    Cell binding;    Point mutation;    Cell growth;    Crystal structure;    Saccharomyces cerevisiae;   

DOI  :  10.1371/journal.ppat.1003742

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Adenovirus E4orf4 protein induces the death of human cancer cells and Saccharomyces cerevisiae. Binding of E4orf4 to the B/B55/Cdc55 regulatory subunit of protein phosphatase 2A (PP2A) is required, and such binding inhibits PP2AB55 activity leading to dose-dependent cell death. We found that E4orf4 binds across the putative substrate binding groove predicted from the crystal structure of B55α such that the substrate p107 can no longer interact with PP2AB55α. We propose that E4orf4 inhibits PP2AB55 activity by preventing access of substrates and that at high E4orf4 levels this inhibition results in cell death through the failure to dephosphorylate substrates required for cell cycle progression. However, E4orf4 is expressed at much lower and less toxic levels during a normal adenovirus infection. We suggest that in this context E4orf4 largely serves to recruit novel substrates such as ASF/SF2/SRSF1 to PP2AB55 to enhance adenovirus replication. Thus E4orf4 toxicity probably represents an artifact of overexpression and does not reflect the evolutionary function of this viral product.

【 授权许可】

CC BY