Systematic analysis of human kinase genes: a large number of genes and alternative splicing events result in functional and structural diversity.
BACKGROUND
Protein kinases are a well defined family of proteins, characterized by the presence of a common kinase catalytic domain and playing a significant role in many important cellular processes, such as proliferation, maintenance of cell shape, apoptosis. In many members of the family, additional non-kinase domains contribute further specialization, resulting in subcellular localization, protein binding and regulation of activity, among others. About 500 genes encode members of the kinase family in the human genome, and although many of them represent well known genes, a larger number of genes code for proteins of more recent identification, or for unknown proteins identified as kinase only after computational studies.


RESULTS
A systematic in silico study performed on the human genome, led to the identification of 5 genes, on chromosome 1, 11, 13, 15 and 16 respectively, and 1 pseudogene on chromosome X; some of these genes are reported as kinases from NCBI but are absent in other databases, such as KinBase. Comparative analysis of 483 gene regions and subsequent computational analysis, aimed at identifying unannotated exons, indicates that a large number of kinase may code for alternately spliced forms or be incorrectly annotated. An InterProScan automated analysis was performed to study domain distribution and combination in the various families. At the same time, other structural features were also added to the annotation process, including the putative presence of transmembrane alpha helices, and the cystein propensity to participate into a disulfide bridge.


CONCLUSIONS
The predicted human kinome was extended by identifying both additional genes and potential splice variants, resulting in a varied panorama where functionality may be searched at the gene and protein level. Structural analysis of kinase proteins domains as defined in multiple sources together with transmembrane alpha helices and signal peptide prediction provides hints to function assignment. The results of the human kinome analysis are collected in the KinWeb database, available for browsing and searching over the internet, where all results from the comparative analysis and the gene structure annotation are made available, alongside the domain information. Kinases may be searched by domain combinations and the relative genes may be viewed in a graphic browser at various level of magnification up to gene organization on the full chromosome set.
Milanesi
Luciano
L
Biomedical Technologies Institute (ITB), National Research Council, Milan, Italy. luciano.milanesi@itb.cnr.it
Petrillo
Mauro
M
Sepe
Leandra
L
Boccia
Angelo
A
D'Agostino
Nunzio
N
Passamano
Myriam
M
Di Nardo
Salvatore
S
Tasco
Gianluca
G
Casadio
Rita
R
Paolella
Giovanni
G
D000465:Algorithms; D017398:Alternative Splicing; D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002874:Chromosome Mapping; D019295:Computational Biology / Q000379:methods*; D030541:Databases, Genetic; D030562:Databases, Protein; D004220:Disulfides; D005091:Exons; D015971:Gene Expression Regulation, Enzymologic; D014644:Genetic Variation; D016678:Genome; D006801:Humans; D020407:Internet; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D005810:Multigene Family; D010770:Phosphotransferases / Q000235:genetics*; D017434:Protein Structure, Tertiary; D020543:Proteome; D017421:Sequence Analysis; D012984:Software; D013329:Structure-Activity Relationship
D004220:Disulfides; D020543:Proteome; D010770:Phosphotransferases