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: We next set out to explore whether evolutionary insights could be derived from these results. It has previously been observed that the evolution of the kinase domain as a whole is not an accurate reflection of how different kinases have evolved different peptide specificities (Miller et al., 2008, Rausell et al., 2010). Thus, we speculated that a Dendrogram based solely on residues identified as DoS by KINspect could carry significant differences compared to a domain-wide phylogenetic tree. Indeed, Figure 5A (and Figure S5) illustrates how the relationships between kinases (and even between kinase families) appear to deviate when addressed from the DoS’ perspective. This DoS-based tree (Figures 5A and S5) illustrates interesting differences including: (1) the embedding of kinase families within other families, such as in the case of the PKN family, embedded within the PKC family, (2) clustering of seemingly unrelated families, such as the Yank and GRK families, or (3) the splitting of families in two sets displaying marked amino acid differences on their DoS, such as in the case of the Ste20 family.
Affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark. Electronic address: firstname.lastname@example.org.