The Molecular Basis of Aichi Virus 3A Protein Activation of Phosphatidylinositol 4 Kinase IIIbeta, PI4KB, through ACBD3.
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McPhail JA, Ottosen EH, Jenkins ML, Burke JE
The Molecular Basis of Aichi Virus 3A Protein Activation of Phosphatidylinositol 4 Kinase IIIbeta, PI4KB, through ACBD3.
Structure. 2017 Jan 3;25(1):121-131. doi: 10.1016/j.str.2016.11.016. Epub 2016 Dec 15.
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- Abstract
Phosphatidylinositol 4-kinase III beta (PI4KIIIbeta) is an essential enzyme in mediating membrane transport, and plays key roles in facilitating viral infection. Many pathogenic positive-sense single-stranded RNA viruses activate PI4KIIIbeta to generate phosphatidylinositol 4-phosphate (PI4P)-enriched organelles for viral replication. The molecular basis for PI4KIIIbeta activation during viral infection has remained largely unclear. We describe the biochemical reconstitution and characterization of the complex of PI4KIIIbeta with the Golgi protein Acyl-coenzyme A binding domain containing protein 3 (ACBD3) and Aichi virus 3A protein on membranes. We find that 3A directly activates PI4KIIIbeta, and this activation is sensitized by ACBD3. The interfaces between PI4KIIIbeta-ACBD3 and ACBD3-3A were mapped with hydrogen-deuterium exchange mass spectrometry (HDX-MS). Determination of the crystal structure of the ACBD3 GOLD domain revealed a unique N terminus that mediates the interaction with 3A. Rationally designed complex-disrupting mutations in both ACBD3 and PI4KIIIbeta completely abrogated the sensitization of 3A activation by ACBD3.