The Protein kinase superfamily controls signaling pathways by phosphorylating downstream proteins. The expertise of these enzymes lies in their ability to work as an ON/OFF molecular switch to regulate a signal. Perturbations in this switch cause cancers and diseases. Recently, these ON/OFF states have been linked to the assembly/disassembly of spatially conserved hydrophobic motifs at the kinase core called the 'spines'. These are the Regulatory (R) and the Catalytic (C) spines that run through the kinase domain. In the present study we show how selectively trapping the assembly of R-or C-spines allows us to lock a kinase in its ON or OFF state. These locked activation states serve as tools to study aspects of kinase mechanism not elucidated so far. The C-spine Phe mutants are locked in the OFF state. These serve as 'pseudo-kinases' that elucidate catalysis-independent functions of canonical kinases. The pseudo-kinases  bind their cognate binding partners as scaffolds to activate them. The R-spine Phe mutants are constitutively active and locked in the ON state. These Phe mutations explain the role of cancer drivers that evade regulatory mechanisms that switch a kinase ON.

Tweaking the spines of kinase structures

248th National Meeting (2014)

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