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. 2005 Mar 16:5:6.
doi: 10.1186/1472-6807-5-6.

A comprehensive update of the sequence and structure classification of kinases

Sara Cheek  1 , Krzysztof Ginalski, Hong Zhang, Nick V Grishin
Affiliations

A comprehensive update of the sequence and structure classification of kinases

Sara Cheek et al. BMC Struct Biol. .

Abstract

Background: A comprehensive update of the classification of all available kinases was carried out. This survey presents a complete global picture of this large functional class of proteins and confirms the soundness of our initial kinase classification scheme.

Results: The new survey found the total number of kinase sequences in the protein database has increased more than three-fold (from 17,310 to 59,402), and the number of determined kinase structures increased two-fold (from 359 to 702) in the past three years. However, the framework of the original two-tier classification scheme (in families and fold groups) remains sufficient to describe all available kinases. Overall, the kinase sequences were classified into 25 families of homologous proteins, wherein 22 families (approximately 98.8% of all sequences) for which three-dimensional structures are known fall into 10 fold groups. These fold groups not only include some of the most widely spread proteins folds, such as the Rossmann-like fold, ferredoxin-like fold, TIM-barrel fold, and antiparallel beta-barrel fold, but also all major classes (all alpha, all beta, alpha+beta, alpha/beta) of protein structures. Fold predictions are made for remaining kinase families without a close homolog with solved structure. We also highlight two novel kinase structural folds, riboflavin kinase and dihydroxyacetone kinase, which have recently been characterized. Two protein families previously annotated as kinases are removed from the classification based on new experimental data.

Conclusion: Structural annotations of all kinase families are now revealed, including fold descriptions for all globular kinases, making this the first large functional class of proteins with a comprehensive structural annotation. Potential uses for this classification include deduction of protein function, structural fold, or enzymatic mechanism of poorly studied or newly discovered kinases based on proteins in the same family.

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Figures

Figure 1
Figure 1
Two new kinase folds. a) Riboflavin kinase (PDB|1q9s [8]). Loops L1 and L2 are shown in magenta. Residues 1 (Pro33) and 2 (Phe97) interact with the adenine ring of the nucleotide. Residues 3 (Thr34) and 4 (Asn36) coordinate the Mg2+ cation. Residues 4 (Asn36) and 5 (Tyr98) interact with the phosphate tail of the nucleotide. In this and all other structure figures, the ATP analog is colored orange, substrate molecules are purple, and Mg2+ cations are green balls. Ribbon diagrams were made using the MOLSCRIPT [57] program. b) Dihydroxyacetone kinase nucleotide-binding domain (PDB|1un9 [9]). Residues 1 (Leu435), 2 (Thr476), and 3 (Met477) pack around the adenine ring of the nucleotide. Residues 4 (Ser431) and 5 (Ser432) interact with the phosphate tail of the nucleotide. Residues 6 (Asp380), 7 (Asp385), and 8 (Asp387) are involved in coordinating the two Mg2+ cations. Dashed lines indicate disordered regions in the structure.
Figure 2
Figure 2
Glycerate kinase structures. a) Neisseria meningitides glycerate kinase (PDB|1to6), a representative of first glycerate kinase family (previously Group 15). Highly conserved amino acids with side chains pointing into the presumed active site include 6 residues from the Rossmann-like domain (1 – Asp8, 2 – Lys11, 3 – Asp43, 6 – Glu286, 7 – Asp290, and 8 – Lys297) and 2 residues from the inserted domain (4 – Asp191 and 5 – Gln209). Glycine rich loops are shown in magenta. Sulfates are shown in ball-and-stick representation. b) Thermotoga maritima putative glycerate kinase (PDB|1o0u), a member of the second glycerate kinase family (previously Group 16, now Group 10). Highly conserved amino acids with side chains pointing into the presumed active site include 2 residues from the Rossmann-like domain (1 – Lys47 and 2 – Asp189) and 4 residues from the C-terminal domain (3 – Glu312, 4 – Arg325, 5 – Asp351, and 6 – Asn407). The glycine rich loop is shown in magenta.
Figure 3
Figure 3
Structure of inositol polyphosphate kinases. a) Inositol 1,4,5-trisphosphate 3-kinase (I3P3K) (PDB|1w2c [12]) adopts a lipid kinase/protein kinase-like fold. Common core of lipid kinases, eukaryotic protein kinases, and I3P3K is shown in blue (α-helices) and yellow (β-strands); additional elements are grey. Residue 1 (Lys209) interacts with the nucleotide's phosphate tail, residue 2 (Glu215) stabilizes the orientation of residue 1, residue 3 (Asp262) binds the sugar group of ATP, residue 4 (Lys264) likely interacts with the γ-phosphate during transfer, and residues 5 (Ser399) and 6 (Asp416) are both likely involved in coordinating two Mg2+ cations. Mn2+ is shown as a green ball and inositol 1,4,5-trisphosphate is shown in purple. b) Multiple sequence alignment of I3P3K (gi|10176869, PDB|1w2c, PDB|1tzd) and I5P2K (gi|6320521) with two related kinase families: lipid kinase representative PIPK (PDB|1bo1 [14]; Family 1b) and protein kinase representative twitchin kinase (PDB|1koa [58]; Family 1a). Italics denote α-helical regions for which the register of structure-based alignment cannot be obtained unequivocally due to significant structural divergence. Critical active site residues are indicated by white bold text highlighted in black/magenta, and are numbered the same as in panel (a). Magenta highlighting indicates residues that perform equivalent roles and are found in equivalent spatial locations, but do not align closely in sequence between the lipid kinase and protein kinase families. In this and other multiple alignments, sequences are labelled according to the NCBI gene identification (gi) number or PDB code and an abbreviation of the species name. Abbreviations in this alignment are as follows: Ag Anopheles gambiae, Am Apis mellifera, At Arabidopsis thaliana, Ce Caenorhabditis elegans, Dh Debaryomyces hansenii, Dm Drosophila melanogaster, Gg Gallus gallus, Gz Gibberella zeae, Hs Homo sapiens, Mg Mytilus galloprovincialis, Mm Mus musculus, Rn Rattus norvegicus, Sc Saccharomyces cerevisiae. First and last residue numbers are indicated before and after each sequence. Numbers of excluded residues are specified in square brackets. Residue conservation is denoted with the following scheme: mostly hydrophobic positions, highlighted yellow; mostly charged/polar positions, highlighted grey; small residues, red bold text. Locations of predicted (gi|6320521, gi|10176869) and observed (PDB|1w2c_A, PDB|1tzd_B, PDB|1bo1_A, PDB|1koa) secondary structure elements (E, β-strand; H, α-helix) are marked above the sequences (with the exception of gi|10176869 which is shown below the sequence) in italics and normal font, respectively.
Figure 4
Figure 4
Eukaryotic pantothenate kinase is a ribonuclease H-like kinase. Multiple sequence alignment for representative sequences of the pantothenate kinase family and two related ribonuclease H-like families with known structure (2-hydroxyglutaryl-CoA dehydratase component A (PDB|1hux [20]) and hexokinase I (PDB|1dgk [59])) is shown. The PHOSPHATE 1, PHOSPHATE 2, and ADENOSINE motifs are indicated by dashed boxes. Abbreviations of species names are as follows: Af Acidaminococcus fermentans, At Arabidopsis thaliana, Bc Bacillus cereus, Ca Clostridium acetobutylicum, Ce Caenorhabditis elegans, Dm Drosophila melanogaster, En Emericella nidulans, Hs Homo sapiens, Mm Mus musculus, Mt Methanothermobacter thermautotrophicus, Pa Pichia angusta, Ta Thauera aromatica, Tt Thermoanaerobacter tengcongensis. Locations of predicted (gi|4191500) and observed (PDB|1hux_A, PDB|1dgk_N) secondary structure elements (E, β-strand; H, α-helix) are marked above the sequences in italics and normal font, respectively.
Figure 5
Figure 5
Second and third domains of polyphosphate kinase are homologous to phospholipase D. Multiple sequence alignment for representative sequences of polyphosphate kinase (gi|7465499, Group 11) and the phospholipase D family (PDB|1bys [24]) is shown. Highly conserved active site residues are highlighted in black and shown in white bold text. Abbreviations of species names are as follows: Bh Bacillus halodurans, Bj Bradyrhizobium japonicum, Ca Clostridium acetobutylicum, Ch Cytophaga hutchinsonii, Dh Desulfitobacterium hafniense, Ec Escherichia coli, Pa Pseudomonas aeruginosa, Rp Rickettsia prowazekii, St Salmonella typhimurium, Wg Wigglesworthia glossinidia brevipalpis. Locations of predicted (gi|7465499) and observed (PDB|1bys_A) secondary structure elements (E, β-strand; H, α-helix) are marked above the sequences in italics and normal font, respectively.
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