title: Characterization of pathogenic germline mutations in human protein kinases.
abstract: BACKGROUND
  Protein Kinases are a superfamily of proteins involved in crucial cellular processes such as cell cycle regulation and signal transduction. Accordingly, they play an important role in cancer biology. To contribute to the study of the relation between kinases and disease we compared pathogenic mutations to neutral mutations as an extension to our previous analysis of cancer somatic mutations. First, we analyzed native and mutant proteins in terms of amino acid composition. Secondly, mutations were characterized according to their potential structural effects and finally, we assessed the location of the different classes of polymorphisms with respect to kinase-relevant positions in terms of subfamily specificity, conservation, accessibility and functional sites.
  
  
  RESULTS
  Pathogenic Protein Kinase mutations perturb essential aspects of protein function, including disruption of substrate binding and/or effector recognition at family-specific positions. Interestingly these mutations in Protein Kinases display a tendency to avoid structurally relevant positions, what represents a significant difference with respect to the average distribution of pathogenic mutations in other protein families.
  
  
  CONCLUSIONS
  Disease-associated mutations display sound differences with respect to neutral mutations: several amino acids are specific of each mutation type, different structural properties characterize each class and the distribution of pathogenic mutations within the consensus structure of the Protein Kinase domain is substantially different to that for non-pathogenic mutations. This preferential distribution confirms previous observations about the functional and structural distribution of the controversial cancer driver and passenger somatic mutations and their use as a proxy for the study of the involvement of somatic mutations in cancer development.
authors: Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernandez Almagro 3, E28029 Madrid, Spain.
authors: Jose M G
authors: JM
authors: Izarzugaza
authors: Lisa E M
authors: LE
authors: Hopcroft
authors: Anja
authors: A
authors: Baresic
authors: Christine A
authors: CA
authors: Orengo
authors: Andrew C R
authors: AC
authors: Martin
authors: Alfonso
authors: A
authors: Valencia
mesh_terms: D018095:Germ-Line Mutation; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000235:genetics; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D017354:Point Mutation; D011485:Protein Binding; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
chemical_list: C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D011494:Protein Kinases