Unmasking Determinants of Specificity in the Human Kinome

Pau Creixell, Antonio Palmeri, Chad J. Miller, Hua Jane Lou, Cristina Costa Santina, Morten Nielsen, Benjamin E. Turk, Rune Linding

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    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]).
    Original languageEnglish
    Issue number1
    Pages (from-to)187-201
    Number of pages15
    Publication statusPublished - 2015

    Bibliographical note

    This is an open access article under the CC BY license http://creativecommons.org/licenses/by/4.0/).

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