Unmasking determinants of specificity in the human kinome.
Bottom Line: 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.
Affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark. Electronic address: email@example.com.Show MeSH
Related in: MedlinePlus
Mentions: Despite the crucial importance of signaling fidelity in biological organization and cellular responses to environmental cues, our perception of how peptide specificity is encoded in the kinase domain has been highly fragmented and biased toward certain kinase families, non-human species, or a subset of kinase domain residues (e.g., those close to the peptide substrate). Here, we developed a data-driven systematic approach to investigate the presence of DoS residues throughout the human kinome, experimentally validated several of these DoS, which together with those shown in the accompanying article (Creixell et al., 2015) encode specificity for the five residue positions most critical for specificity in the peptide substrate (P-3, P-2, P0, P+1, P+2), and identified a distributed, but interconnected, network of DoS in different parts of the kinase domain. In contrast to previous studies, our results suggest specificity is driven by a larger number of residues and a more distributed network of typically non-conserved sets of residues than previously appreciated (Figures 7A and 7B).
Affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark. Electronic address: firstname.lastname@example.org.