Functional and Structural Mimicry of Cellular Protein Kinase A Anchoring Proteins by a Viral Oncoprotein
Cason R King1, Michael J Cohen1, Gregory J Fonseca1
1Department of Microbiology & Immunology, University of Western Ontario, London, Ontario, Canada.
Abstract:
The oncoproteins of the small DNA tumor viruses interact with a plethora of cellular regulators to commandeer control of the infected cell. During infection, adenovirus E1A deregulates cAMP signalling and repurposes it for activation of viral gene expression. We show that E1A structurally and functionally mimics a cellular A-kinase anchoring protein (AKAP). E1A interacts with and relocalizes protein kinase A (PKA) to the nucleus, likely to virus replication centres, via an interaction with the regulatory subunits of PKA. Binding to PKA requires the N-terminus of E1A, which bears striking similarity to the amphipathic α-helical domain present in cellular AKAPs. E1A also targets the same docking-dimerization domain of PKA normally bound by cellular AKAPs. In addition, the AKAP like motif within E1A could restore PKA interaction to a cellular AKAP in which its normal interaction motif was deleted. During infection, E1A successfully competes with endogenous cellular AKAPs for PKA interaction. E1A's role as a viral AKAP contributes to viral transcription, protein expression and progeny production. These data establish HAdV E1A as the first known viral AKAP. This represents a unique example of viral subversion of a crucial cellular regulatory pathway via structural mimicry of the PKA interaction domain of cellular AKAPs.
Insights
Adenovirus E1A protein acts as a viral A-kinase anchoring protein (AKAP), mimicking cellular AKAPs to hijack protein kinase A (PKA) signaling. This viral AKAP activity is crucial for efficient viral gene expression and replication.
Area of Science:
- Virology
- Molecular Biology
- Cellular Signaling
Background:
- Small DNA tumor viruses utilize oncoproteins to manipulate host cell processes.
- Adenovirus E1A protein is known to deregulate cAMP signaling for viral gene activation.
Purpose of the Study:
- To investigate the mechanism by which adenovirus E1A protein interacts with and deregulates cellular signaling pathways.
- To determine if E1A mimics cellular regulators to control host cell machinery.
Main Methods:
- Structural and functional analysis of adenovirus E1A protein.
- Investigating interactions between E1A and protein kinase A (PKA) regulatory subunits.
- Assessing the role of E1A in competing with cellular A-kinase anchoring proteins (AKAPs).
Main Results:
- Adenovirus E1A protein structurally and functionally mimics cellular AKAPs.
- E1A interacts with PKA regulatory subunits, relocating PKA to the nucleus.
- E1A competes with endogenous AKAPs for PKA binding, promoting viral transcription and replication.
Conclusions:
- Adenovirus E1A functions as the first identified viral AKAP.
- E1A's mimicry of AKAP domains represents a novel strategy for viral subversion of cellular signaling pathways.
- This mechanism is critical for efficient viral gene expression and progeny production.
Related Concept Videos
Viral Structure
Assembly of Signaling Complexes
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
PI3K/mTOR/AKT Signaling Pathway
cAMP-dependent Protein Kinase Pathways
Protein Kinases and Phosphatases
Protein Kinases and Phosphatases
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...


