Granulovirus PK-1 kinase activity relies on a side-to-side dimerization mode centered on the regulatory αC helix
Oliver MR., Horne CR., Shrestha S., Keown JR., Liang L-Y., Young SN., Sandow JJ., Webb AI., Goldstone DC., Lucet IS., Kannan N., Metcalf P., Murphy JM.
<jats:title>Abstract</jats:title><jats:p>The life cycle of <jats:italic>Baculoviridae</jats:italic> family insect viruses depends on the viral protein kinase, PK-1, to phosphorylate the regulatory protein, p6.9, to induce baculoviral genome release. Here, we report the crystal structure of <jats:italic>Cydia pomenella</jats:italic> granulovirus PK-1, which, owing to its likely ancestral origin among host cell AGC kinases, exhibits a eukaryotic protein kinase fold. PK-1 occurs as a rigid dimer, where an antiparallel arrangement of the αC helices at the dimer core stabilizes PK-1 in a closed, active conformation. Dimerization is facilitated by C-lobe:C-lobe and N-lobe:N-lobe interactions between protomers, including the domain-swapping of an N-terminal helix that crowns a contiguous β-sheet formed by the two N-lobes. PK-1 retains a dimeric conformation in solution, which is crucial for catalytic activity. Our studies raise the prospect that parallel, side-to-side dimeric arrangements that lock kinase domains in a catalytically-active conformation could function more broadly as a regulatory mechanism among eukaryotic protein kinases.</jats:p>