Kinases play key roles in cellular signaling events related to activation, development, and cell growth. Despite high sequence and structural homology among the tyrosine kinases, there is evidence that different families employ distinct regulatory mechanisms. Here we focus on the two largest families of non-receptor tyrosine kinases, the Tec kinases that are expressed in cells of hematopoietic lineage and the more widely expressed Src kinases.  Opposite regulatory mechanisms control the activity of the Tec and Src kinases; the Tec family kinase domains are inactive without assembly of the adjacent regulatory domains whereas the Src kinase domains are autoinhibited by assembly of the regulatory domains. Using a combination of molecular dynamic simulations, biochemical assays, and biophysical approaches including NMR and HDXMS, we have identified a single residue that acts as a 'wedge', holding the Tec kinase domains in their inactive conformation. We also describe the allosteric features provided by the regulatory domains that overcome the inhibitory 'wedge' resulting in stabilization of the active kinase domain. These findings provide molecular level insight into how a kinase can achieve 'inactive by default' status, effectively delegating activation to regions outside the kinase domain.

Distinct regulatory features of the Tec family kinases

248th National Meeting (2014)

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