Biophysical and functional analyses suggest that adenovirus E4-ORF3 protein requires higher-order multimerization to function against promyelocytic leukemia protein nuclear bodies.

The Journal of Biological Chemistry
Vadim PatsaloPatrick Hearing

Abstract

The early region 4 open reading frame 3 protein (E4-ORF3; UniProt ID P04489) is the most highly conserved of all adenovirus-encoded gene products at the amino acid level. A conserved attribute of the E4-ORF3 proteins of different human adenoviruses is the ability to disrupt PML nuclear bodies from their normally punctate appearance into heterogeneous filamentous structures. This E4-ORF3 activity correlates with the inhibition of PML-mediated antiviral activity. The mechanism of E4-ORF3-mediated reorganization of PML nuclear bodies is unknown. Biophysical analysis of the purified WT E4-ORF3 protein revealed an ordered secondary/tertiary structure and the ability to form heterogeneous higher-order multimers in solution. Importantly, a nonfunctional E4-ORF3 mutant protein, L103A, forms a stable dimer with WT secondary structure content. Because the L103A mutant is incapable of PML reorganization, this result suggests that higher-order multimerization of E4-ORF3 may be required for the activity of the protein. In support of this hypothesis, we demonstrate that the E4-ORF3 L103A mutant protein acts as a dominant-negative effector when coexpressed with the WT E4-ORF3 in mammalian cells. It prevents WT E4-ORF3-mediated PML track forma...Continue Reading

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Citations

Jun 2, 2016·Proceedings of the National Academy of Sciences of the United States of America·Sook-Young Sohn, Patrick Hearing
Apr 9, 2014·PloS One·April Renee Sandy GochaJoanna Groden
Feb 20, 2015·Journal of Virology·Roberta L TurnerDavid A Ornelles
Sep 22, 2016·MBio·Sook-Young Sohn, Patrick Hearing
Nov 14, 2019·FEBS Letters·Sook-Young Sohn, Patrick Hearing
Feb 28, 2019·MBio·Sook-Young Sohn, Patrick Hearing
Dec 29, 2020·Virus Research·Samuel HofmannSabrina Schreiner

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