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Crystal Structure of the α-Kinase Domain of Dictyostelium Myosin Heavy Chain Kinase A

Structural analysis identifies features of atypical serine-threonine kinases that may account for their different activities relative to those of conventional kinases. In the Loop Conventional serine-threonine protein kinases constitute a huge family of enzymes that regulate many processes in the cell. In contrast, the family of α-kinases is far smaller and consists of atypical kinases that regulate a much more restricted range of functions. Ye et al. have now solved the crystal structure of a prototypical member of the α-kinase family and identified features of the active site of these enzymes that may account for their different activities relative to those of the conventional kinases. Ye et al. solved the crystal structures of the catalytic domain of Dictyostelium myosin II heavy chain kinase A (MHCK A) bound to various nucleotides and compared them to structures of the kinase domains of TRPM7, another α-kinase, and PKA, a conventional protein kinase. In addition to demonstrating that MHCK A and TRPM7 share an almost identical core catalytic domain, solving these structures has identified critical features that distinguish the α-kinases from the conventional protein kinases. In particular, the authors identified a metal ion-binding loop that regulates access to the active site and an aspartylphosphate residue that may act as an intermediate in the phosphorylation of substrates. Dictyostelium discoideum myosin II heavy chain kinase A (MHCK A) disrupts the assembly and cellular activity of bipolar filaments of myosin II by phosphorylating sites within its α-helical, coiled-coil tail. MHCK A is a member of the atypical α-kinase family of serine and threonine protein kinases and displays no sequence homology to typical eukaryotic protein kinases. We report the crystal structure of the α-kinase domain (A-CAT) of MHCK A. When crystallized in the presence of adenosine triphosphate (ATP), A-CAT contained adenosine monophosphate (AMP) at the active site. However, when crystallized in the presence of ATP and a peptide substrate, which does not appear in the structure, adenosine diphosphate (ADP) was found at the active site and an invariant aspartic acid residue (Asp766) at the active site was phosphorylated. The aspartylphosphate group was exposed to the solvent within an active-site pocket that might function as a docking site for substrates. Access to the aspartylphosphate was regulated by a conformational switch in a loop that bound to a magnesium ion (Mg2+), providing a mechanism that allows α-kinases to sense and respond to local changes in Mg2+.