A New Crucial Protein Interaction Element That Targets the Adenovirus E4-ORF1 Oncoprotein to Membrane Vesicles
dc.contributor.author | Chung, Sang-Hyuk | |
dc.contributor.author | Frese, Kristopher K. | |
dc.contributor.author | Weiss, Robert S. | |
dc.contributor.author | Prasad, B. V. Venkataram | |
dc.contributor.author | Javier, Ronald T. | |
dc.date.accessioned | 2020-03-10T17:11:56Z | |
dc.date.available | 2020-03-10T17:11:56Z | |
dc.date.issued | 2007-05 | |
dc.description.abstract | Human adenovirus type 9 exclusively elicits mammary tumors in experimental animals, and the primary oncogenic determinant of this virus is the E4-ORF1 oncogene, as opposed to the well-known E1A and E1Boncogenes. The tumorigenic potential of E4-ORF1, as well as its ability to oncogenically stimulate phosphatidylinositol 3-kinase (PI3K), depends on a carboxyl-terminal PDZ domain-binding motif (PBM) that mediates interactions with several different membrane-associated cellular PDZ proteins, including MUPP1, PATJ, MAGI-1, ZO-2, and Dlg1. Nevertheless, because certain E4-ORF1 mutations that alter neither the sequence nor the function of the PBM abolish E4-ORF1-induced PI3K activation and cellular transformation, we reasoned that E4-ORF1 must possess an additional crucial protein element. In the present study, we identified seven E4-ORF1 amino acid residues that define this new element, designated domain 2, and showed that it mediates binding to a 70-kDa cellular phosphoprotein. We also discovered that domain 2 or the PBM independently promotes E4-ORF1 localization to cytoplasmic membrane vesicles and that this activity of domain 2 depends on E4-ORF1 trimerization. Consistent with the latter observation, molecular-modeling analyses predicted that E4-ORF1 trimerization brings together six out of seven domain 2 residues at each of the three subunit interfaces. These findings importantly demonstrate that PI3K activation and cellular transformation induced by E4-ORF1 require two separate protein interaction elements, domain 2 and the PBM, each of which targets E4-ORF1 to vesicle membranes in cells. | |
dc.identifier.citation | Copyright 2007 Journal of Virology. Recommended citation: Chung, Sang-Hyuk, Kristopher K. Frese, Robert S. Weiss, BV Venkataram Prasad, and Ronald T. Javier. "A new crucial protein interaction element that targets the adenovirus E4-ORF1 oncoprotein to membrane vesicles." Journal of virology 81, no. 9 (2007): 4787-4797. DOI: 10.1128/JVI.02855-06. URL: https://jvi.asm.org/content/81/9/4787/article-info. Reproduced in accordance with the original publisher's licensing terms and with permission from the author(s). | |
dc.identifier.uri | https://hdl.handle.net/10657/5919 | |
dc.language.iso | en_US | |
dc.publisher | Journal of Virology | |
dc.subject | adenovirus | |
dc.subject | mammary tumors | |
dc.subject | E4-ORF1 | |
dc.subject | phosphatidylinositol 3-kinase | |
dc.subject | PDZ domain-binding motif | |
dc.subject | PI 3-kinase | |
dc.title | A New Crucial Protein Interaction Element That Targets the Adenovirus E4-ORF1 Oncoprotein to Membrane Vesicles | |
dc.type | Article |