Abstract
SummaryProtein 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]).
Highlights
Cellular organization and response to external and internal cues relies on swift and precise processing of information through cell signaling networks
We demonstrate that determinants of specificity (DoS) form sparse networks of non-conserved residues spanning distant regions
While other factors contributing to protein interaction specificity at a macro-molecular level have been described (Bhattacharyya et al, 2006; Linding et al, 2007; Remenyi et al, 2005; Scott and Pawson, 2009), the combination of residues in the kinase domain that encode peptide substrate specificity, the so-called determinants of specificity (DoS), have remained largely elusive (Figure 1B)
Summary
Cellular organization and response to external and internal cues relies on swift and precise processing of information through cell signaling networks High fidelity in these circuits depends critically on the recognition and phosphorylation of specific substrates by protein kinases, and perturbations of this cellular system have been linked to significant evolutionary transitions (Capra et al, 2012; Skerker et al, 2008; Tan et al, 2009; Zarrinpar et al, 2003), as well as to disease progression, in particular, in cancer (Borrello et al, 1995; Creixell et al, 2012; Marengere et al, 1994; Santoro et al, 1995; Songyang et al, 1995). Even though some structural studies have helped identify residues that are in close contact with the substrate peptide which likely influence specificity (Brinkworth et al, 2003; Ellis and Kobe, 2011; Hanks and Hunter, 1995; Mok et al, 2010; Nolen et al, 2004), these studies were largely focused on specific kinase families and/or non-human species as well as limited in scope by the small number of kinase-peptide structures currently available and an inability to capture potentially long-range DoS
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