Article abstract
Nature Structural & Molecular Biology 16, 624 - 630 (2009)
Published online: 24 May 2009 | doi:10.1038/nsmb.1606
PKC maturation is promoted by nucleotide pocket occupation independently of intrinsic kinase activity
Angus J M Cameron1, Cristina Escribano1,2, Adrian T Saurin1, Brenda Kostelecky3 & Peter J Parker1,4
Abstract
The protein kinase C (PKC) Ser/Thr kinases account for 
2% of the human kinome and regulate diverse cellular behaviors. PKC catalytic activity requires priming phosphorylations at three conserved sites within the kinase domain. Here we demonstrate that priming of PKC is dependent on the conformation of the nucleotide binding pocket but not on its intrinsic kinase activity. Inactive ATP binding site mutants are unprimed, but they become phosphorylated upon occupancy of the ATP binding pocket with inhibitors of PKC. We have exploited this property to screen for PKC inhibitors in vivo. Further, we generated a distinct class of kinase-inactive mutants that maintain the integrity of the ATP binding pocket; such mutants are constitutively primed and functionally distinct from ATP binding site mutants. These data demonstrate that autophosphorylation is not required for PKC priming and show how ATP pocket occupation can enable a kinase to mature as well as function.
- Protein Phosphorylation Laboratory, Cancer Research UK, London Research Institute, London, UK.
- Centro de Investigaciones Biológicas, Madrid, Spain.
- Structural Biology Laboratory, London Research Institute, Cancer Research UK, London, UK.
- Division of Cancer Studies, King's College London, London, UK.
Correspondence to: Peter J Parker1,4 e-mail: peter.parker@cancer.org.uk
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