![]() ![]() The gappy regions are usually present between major elements of secondary structure, where the family members may have widely divergent sequence loop lengths due to numerous insertions that occurred in different lineages of family members. This is true of the alignment used to produce the kinome tree of Manning et al. This includes the conformations of active and inactive kinases 16, 17, 18, predictions of substrate specificity 19, and analysis of kinase-drug interactions 20, 21.Ī common problem in multiple sequence alignments of large, diverse protein families is that they are very ‘gappy,’ i.e., containing many gap characters in every sequence in order to align inserted segments of different lengths that may be present in only a small subset of the sequences. Multiple sequence alignments of kinases have been used to extend structural and functional information from the kinases with known structures to those without known structures. The accompanying poster and image of this tree is still widely used in scientific papers and presentations on kinases 15. built a phylogenetic tree of 491 typical kinase domains from a multiple sequence alignment created without using any kind of structural information 5. In addition, there are proteins that do not appear to share an evolutionary relationship with typical kinases that also phosphorylate proteins, such as pyruvate dehydrogenase kinases 12.įor any large protein family, an accurate multiple sequence alignment is the basis of an accurate phylogeny 13 and structural and functional inferences 14. Some of these are distantly related to the typical kinase domain, thus making them a superfamily, including Alpha kinases 7, ADCK kinases 8, RIO kinases 9, FAM20C kinases 10, and the PI3-PI4 kinase family, which contains the protein kinases ATM, ATR, and MTOR 11. Uniprot identifies 29 atypical human kinases. ![]() The annotation of the human genome has improved since the Manning paper currently Uniprot identifies 483 human proteins containing 496 typical kinase domains ( ). In 2002, Manning and coworkers identified 518 kinase genes in the human kinome 5 which they divided into 478 typical kinase genes (13 of them containing two kinase domains, for a total of 491 domains) and 40 atypical kinase genes. The active site is located between the two lobes where the activation and catalytic loops form the ATP and substrate binding sites. The vast majority of human kinases come from one very large, diverse family that share a common fold consisting of an N-terminal lobe, composed of five β-sheet strands and an α-helix called the C-helix, and a C-terminal lobe comprising six α-helices 6. Protein kinase activity is found in a number of protein families and superfamilies in the human proteome. Humans have over 500 genes that catalyze the phosphorylation of proteins, collectively called the ‘kinome’ 5. Mutations in kinases that lead to gain of function are frequently observed in many cancer types 3, 4, while mutations may also result in drug resistance rendering existing drugs inefficient 3. Protein kinases catalyze the transfer of a phosphoryl group from an ATP molecule to substrate proteins 1, and are crucial for cellular signaling pathways 2. These kinases comprise the Aurora kinases, Polo kinases, and calcium/calmodulin-dependent kinase kinases. A new phylogeny of the protein kinase domains in the human genome based on our alignment indicates that ten kinases previously labeled as “OTHER” can be confidently placed into the CAMK group. The remaining inaccuracy comes from a few structures with shifted elements of secondary structure, and from the boundaries of aligned and unaligned regions, where compromises need to be made to encompass the majority of kinases. From pairwise, all-against-all alignment of 272 human kinase structures, we estimate the accuracy of our MSA to be 97%. The aligned blocks contain well-conserved elements of secondary structure and well-known functional motifs, such as the DFG and HRD motifs. The alignment is arranged in 17 blocks of conserved regions and unaligned blocks in between that contain insertions of varying lengths present in only a subset of kinases. We present a parsimonious, structure-based multiple sequence alignment (MSA) of 497 human protein kinase domains excluding atypical kinases. The key factor in accurate inference by homology is an accurate sequence alignment. Studies on the structures and functions of individual kinases have been used to understand the biological properties of other kinases that do not yet have experimental structures. ![]()
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