Abstract
BackgroundA 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.ResultsThe 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 (~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 β-barrel fold, but also all major classes (all α, all β, α+β, α/β) 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.ConclusionStructural 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.
Highlights
A comprehensive update of the classification of all available kinases was carried out
In order to investigate the relationship between structural fold and functional specificities in kinases, we carried out a comprehensive analysis of all available kinase structures and sequences [1] three years ago
59,402 sequences are classified into 25 families of homologous kinases. These kinase families are further assembled into 12 fold groups based on similarity of structural fold. 22 of the 25 families belong to 10 fold groups for which the structural fold is known
Summary
A comprehensive update of the classification of all available kinases was carried out. Despite that all kinases use the same phosphate donor (in most cases, ATP) and catalyze apparently the same phosphoryl transfer reaction, they display remarkable diversity in their structural folds and substrate recognition mechanisms. This is probably due largely to the extraordinarily diverse nature of the structures and properties of their substrates. In order to investigate the relationship between structural fold and functional specificities in kinases, we carried out a comprehensive analysis of all available kinase structures and sequences [1] three years ago This analysis surveyed more than 17,000 kinase sequences, which were classified into 30 families of homologous proteins. We were subsequently able to use this kinase classification scheme to analyze various aspects of kinase function and evolution, such as the shared catalytic and nucleotide substrate binding mechanisms across different kinase families and folds
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