title: Unmasking determinants of specificity in the human kinome.
abstract: Protein kinases control cellular responses to environmental cues by swift and accurate signal processing. Breakdowns in this high-fidelity capability are a driving force in cancer and other diseases. Thus, our limited understanding of which amino acids in the kinase domain encode substrate specificity, the so-called determinants of specificity (DoS), constitutes a major obstacle in cancer signaling. Here, we systematically discover several DoS and experimentally validate three of them, named the αC1, αC3, and APE-7 residues. We demonstrate that DoS form sparse networks of non-conserved residues spanning distant regions. Our results reveal a likely role for inter-residue allostery in specificity and an evolutionary decoupling of kinase activity and specificity, which appear loaded on independent groups of residues. Finally, we uncover similar properties driving SH2 domain specificity and demonstrate how the identification of DoS can be utilized to elucidate a greater understanding of the role of signaling networks in cancer (Creixell et al., 2015 [this issue of Cell]).
authors.affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark. Electronic address: creixell@mit.edu.
authors.forename: Pau
authors.initials: P
authors.lastname: Creixell
authors.affiliation: Centre for Molecular Bioinformatics, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Palmeri
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Miller
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Hua Jane
authors.initials: HJ
authors.lastname: Lou
authors.affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark; Biotech Research & Innovation Centre (BRIC), University of Copenhagen (UCPH), 2200 Copenhagen, Denmark.
authors.forename: Cristina C
authors.initials: CC
authors.lastname: Santini
authors.affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Nielsen
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Turk
authors.affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark; Biotech Research & Innovation Centre (BRIC), University of Copenhagen (UCPH), 2200 Copenhagen, Denmark. Electronic address: linding@lindinglab.org.
authors.forename: Rune
authors.initials: R
authors.lastname: Linding
mesh_terms: D019295:Computational Biology; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000378:metabolism; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity; D018909:src Homology Domains
chemical_list: D011494:Protein Kinases