Trans-autophosphorylation is the most common mode of protein kinase activation and involves two copies of the same kinase dimerizing so that one can phosphorylate the activation loop of the other. The diversity among structures of trans-autophosphorylation dimers supported the view that each kinase evolved a unique mode of recognition. We screened all human kinase crystal structures and identified an expanded set of dimers compatible with trans-autophosphorylation (655 dimers from 143 kinases). These dimers share no conserved structural arrangement, but 85% bury the same helix, alpha-G, at the dimer interface. We validate alpha-G-mediated dimerization by mutagenesis in kinases from each group of the kinome activated by trans-autophosphorylation. Alpha-G substitution impaired or abolished activation of full-length proteins, in cells, in every case. In purified kinase domains, alpha-G substitution disrupted dimerization and autophosphorylation. These data establish that dimerization during trans-autophosphorylation is conserved and is mediated by a common structural element that, surprisingly, does not impose a specific arrangement of the two kinase domains relative to each other. Alpha-G is the least conserved element in the kinase fold, yet is required for activation across both the human kinome and other species, suggesting an ancestral function of the kinase fold.
Botterbusch, S., Huso, V. L., Weingartner, K. A., Tryggvason, G., Tripp, K. W., Green, R., Kavran, J. M.
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