The alpha-kinase family: an exceptional branch on the protein kinase tree

Abstract

The alpha-kinase family represents a class of atypical protein kinases that display little sequence similarity to conventional protein kinases. Early studies on myosin heavy chain kinases in Dictyostelium discoideum revealed their unusual propensity to phosphorylate serine and threonine residues in the context of an alpha-helix. Although recent studies show that some members of this family can also phosphorylate residues in non-helical regions, the name alpha-kinase has remained. During evolution, the alpha-kinase domains combined with many different functional subdomains such as von Willebrand factor-like motifs (vWKa) and even cation channels (TRPM6 and TRPM7). As a result, these kinases are implicated in a large variety of cellular processes such as protein translation, Mg(2+) homeostasis, intracellular transport, cell migration, adhesion, and proliferation. Here, we review the current state of knowledge on different members of this kinase family and discuss the potential use of alpha-kinases as drug targets in diseases such as cancer.

Fig. 1

Phylogenetic analysis of the alpha-kinase family. A PSI-Blast [152] search was done, starting with the TRPM7 alpha-kinase domain and using three iterations, to detect all sequenced alpha-kinases. For those sequences that were detected with PSI-Blast, but that were not detected as having an alpha-kinase domain by SMART [151], reciprocal PSI-Blast searches were performed to ensure that they were indeed homologous alpha-kinases. From the results, species were included so that the major eukaryotic taxa with alpha-kinases would be represented in the tree. Selected sequences were then aligned using ClustalW2 [153]. A phylogenetic tree was generated using PHYML [154] as implemented in Seaview [155]. Bootstrap values of the major branches are indicated. The dashed line separates vertebrate from invertebrate alpha-kinases. Red branches indicate N-terminal alpha-kinases. Alpha-kinases with a typical subdomain architecture are indicated in the colors that refer to the schematic representations in Table 1

Fig. 2

Alpha-kinases: structure and conservation. a Crystal structure of TRPM7 as determined by Yamaguchi et.al. [21]. N-terminus (N) refers to residue G1579 in the human TRPM7 amino acid sequence. Please note that this residue corresponds to G1577 in the mouse sequence. Indicated are domains that resemble the N-terminal lobe (containing P-loop), C-terminal lobe (containing activation loop) and interlobe cleft of CPKs. Conserved residues within the alpha-kinase family (Fig. 3) are indicated in red. b The well-conserved interlobe cleft functions as ATP binding pocket. The ATP molecule (yellow) is positioned within the binding pocket by multiple residues that are well conserved within the alpha-kinase family (red). The indicated residue identities refer to the human TRPM7 amino acid sequence (Fig. 3). c Typical zinc-finger domain within the C-terminal lobe of alpha-kinases. Residues that bind the zinc molecule (green) are well conserved between the alpha-kinase family members (red). The indicated residue identities refer to the human TRPM7 amino acid sequence (Fig. 3)

Fig. 3

Sequence alignment of Dictyostelium and human alpha-kinases. Dictyostelium and human alpha-kinase amino acids sequences corresponding to the human TRPM7 alpha-kinase domain (G1579-T1830) were aligned using ClustalW2 sequence alignment software [153]. Names and species, Dictyostelium discoideum (Dd), Homo sapiens (Hs) are indicated on the left. Conservation of specific residues within this group of alpha-kinases, corrected for missing sequences, is indicated by shadings of blue and a barchart supporting the alignement (0 not conserved, 100 fully conserved). Red bars represent fully conserved residues and are indicated red in Fig. 2. Sequences representing the P-loop and GXGXXG motif are indicated on top. The indicated residue identities refer to the human TRPM7 amino acid sequence