Granulovirus PK-1 kinase activity relies on a side-to-side dimerization mode centered on the regulatory αC helix

Michael R. Oliver, Christopher R. Horne, Safal Shrestha, Jeremy R. Keown, Lung-Yu Liang, Samuel N. Young, Jarrod J. Sandow, Andrew I. Webb, David C. Goldstone, Isabelle S. Lucet, Natarajan Kannan, Peter Metcalf () and James M. Murphy ()
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Michael R. Oliver: University of Auckland
Christopher R. Horne: Walter and Eliza Hall Institute of Medical Research
Safal Shrestha: University of Georgia
Jeremy R. Keown: University of Auckland
Lung-Yu Liang: Walter and Eliza Hall Institute of Medical Research
Samuel N. Young: Walter and Eliza Hall Institute of Medical Research
Jarrod J. Sandow: Walter and Eliza Hall Institute of Medical Research
Andrew I. Webb: Walter and Eliza Hall Institute of Medical Research
David C. Goldstone: University of Auckland
Isabelle S. Lucet: Walter and Eliza Hall Institute of Medical Research
Natarajan Kannan: University of Georgia
Peter Metcalf: University of Auckland
James M. Murphy: Walter and Eliza Hall Institute of Medical Research

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract The life cycle of Baculoviridae 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 Cydia pomenella 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.

Date: 2021
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DOI: 10.1038/s41467-021-21191-7

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