Genomic analysis of the eukaryotic protein kinase superfamily: a perspective

Abstract

Protein kinases with a conserved catalytic domain make up one of the largest 'superfamilies' of eukaryotic proteins and play many key roles in biology and disease. Efforts to identify and classify all the members of the eukaryotic protein kinase superfamily have recently culminated in the mining of essentially complete human genome data.

Figure 1

The ePK catalytic domain. The 12 conserved subdomains are indicated by Roman numerals. The positions of amino-acid residues and motifs highly conserved throughout the ePK superfamily are indicated above the subdomains, using the single-letter amino-acid code with x as any amino acid. Crystal structures show that ePK domains adopt a common fold consisting of amino-terminal and carboxy-terminal lobes connected by a hinge region. Binding of Mg-ATP is largely the function of the amino-terminal lobe and hinge region, while peptide-substrate binding is mediated by the carboxy-terminal lobe. Particularly important for catalytic function are the invariant lysine in subdomain II and the invariant aspartate in subdomain VII that function to anchor and orient ATP, and the invariant aspartate in subdomain VIB which is the likely catalytic base in the phosphotransfer reaction. More detailed discussions of ePK subdomains and conserved residues in relation to crystal structures and catalytic function can be found in [3,4,12,13].

Figure 2

Conserved residues implicated in peptide-substrate recognition. Consensus motifs for the catalytic loop region in subdomain VIB and activation loop region in subdomain VIII were determined for the members of each of the seven major ePK groups with known or likely kinase activity. Invariant residues at a given position are indicated by single upper-case letters. Two upper-case letters at a single position indicate that either of two residues are strictly conserved, the most frequent shown in the top row. Positions in which more than two amino acids are present are indicated with lower-case letters; a single letter indicates that only one residue is highly conserved, two letters indicate that either of two residues are frequently conserved (most frequent on the top row), and 'x' indicating poor positional conservation. Residues highlighted in outline are notably conserved within an ePK group and are thought to function in the recognition of peptide substrates specifically targeted by the members of the group.