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: firstname.lastname@example.org.Show MeSH
Related in: MedlinePlus
Mentions: To investigate the generality of these observations, we explored DoS patterns in another signaling modular protein domain, namely, the SH2 domain. Following a very similar approach as described for the kinase domain, and after identifying the required parameters (Figure S6) appropriately, KINspect identified several SH2 residues that are likely involved in peptide specificity (Figure 6; Movie S2).
Affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark. Electronic address: email@example.com.