PROSITE documentation PDOC51158

Alpha-type protein kinase domain profile

The α-kinases were initially identified because of the experimentally observed ability of EF-2 kinase to phosphorylate elongation factor-2 [1]. It was shown that the EF-2 kinase and the myosin heavy chain kinase A (MHCK A) share a conserved region of about 250 amino acids, the α-kinase domain [2]. The name α-kinase was suggested for the family according to existing evidence that eIF-2 and MHCK A phosphorylate amino acids located within α-helices whereas classical kinase proteins phosphorylate amino acids within loops [3]. α-kinases are multi-domain proteins with a wide variety of domains present in the family. These include: ion-channels, VWFA domains (see <PDOC50234>), WD-repeats (see <PDOC00574>), TPR-repeats (see <PDOC50005>), immunoglobulin-like domains (see <PDOC50835>) and calmodulin binding domains. Members of the α-kinase family share no detectable sequence similarity with the large family of "classical" eukaryotic protein kinases (see <PDOC00100>) [4].

The crystal structure of the α-kinase domain of a TPR channel has been solved [5]. The structure bears a striking resemblance to that of classical protein kinases in the catalytic core as well as to metabolic enzymes with the ATP-grasp domain. As in classical kinase the domain consists of two lobes that bind nucleotide at the interface between them. The N-terminal lobe is very similar in structure to that of classical protein kinases, whereas its C-terminal lobe resembles that of ATP-grasp proteins more closely. A conserved C-terminal glycine rich motif which locates in the region that corresponds to the activation loop of classical kinases is essential for the enzymatic activity [6]. The C-terminal lobe contains a metal ion which is coordinated by two histidines and two cysteines.

Proteins known to contain an α-kinase domain are listed below:

• Eukaryotic elongation factor 2 kinase (EC 2.7.11.20) (eEF-2 kinase). It phosphorylates eukaryotic elongation factor 2.
• Dictyostelium myosin heavy chain kinase A (EC 2.7.11.7) (MHCK A). It phosphorylates a threonine in the C-terminal tail region of myosin II heavy chain. This phosphorylation is critical in regulating the assembly and disassembly of myosin II filament.
• A mammalian subclass of long transient receptor potential channels (TRPM7/ChaK1). An essential ion channel and serine/threonine-protein kinase.
• Mammalian muscle α-kinase.
• Neurospora α-kinase with a VWFA domain.

The profile we developed covers the entire α-kinase domain.