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Unmasking determinants of specificity in the human kinome.

Creixell P, Palmeri A, Miller CJ, Lou HJ, Santini CC, Nielsen M, Turk BE, Linding R - Cell (2015)

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark. Electronic address: creixell@mit.edu.

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Model for DoS Encoding Specificity and Mutations on DoS Perturbing Substrate Specificity(A) By computing the percentage of residues encoding specificity (DoS) and their average distance to the substrate, we conclude that the set of DoS uncovered by KINspect represent a larger and more sparse group of residues and that residues can contribute to peptide specificity even if they are not located in close proximity to the substrate.(B) In this article, we have described the degree to which each residue contribute to specificity on a more quantitative scale and experimentally validated three novel determinants of specificity (Figure 3). Our results also indicate that specificity is loaded onto a set of residues that is less conserved than most others in the domain and where mutations, in cancer or evolution, can easily cause substrate specificity switches by single mutations. As shown in similar signaling systems (Skerker et al., 2008), such mutations represent key turns in how different kinases evolve and occupy separate and sometimes overlapping substrate subspaces. Similar mutations have been seen in cancer (Borrello et al., 1995, Creixell et al., 2012, Santoro et al., 1995, Songyang et al., 1995), despite the fact that this type of mutations has been largely understudied, and their role in the disease remains largely unknown (see Creixell et al., 2015).
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fig7: Model for DoS Encoding Specificity and Mutations on DoS Perturbing Substrate Specificity(A) By computing the percentage of residues encoding specificity (DoS) and their average distance to the substrate, we conclude that the set of DoS uncovered by KINspect represent a larger and more sparse group of residues and that residues can contribute to peptide specificity even if they are not located in close proximity to the substrate.(B) In this article, we have described the degree to which each residue contribute to specificity on a more quantitative scale and experimentally validated three novel determinants of specificity (Figure 3). Our results also indicate that specificity is loaded onto a set of residues that is less conserved than most others in the domain and where mutations, in cancer or evolution, can easily cause substrate specificity switches by single mutations. As shown in similar signaling systems (Skerker et al., 2008), such mutations represent key turns in how different kinases evolve and occupy separate and sometimes overlapping substrate subspaces. Similar mutations have been seen in cancer (Borrello et al., 1995, Creixell et al., 2012, Santoro et al., 1995, Songyang et al., 1995), despite the fact that this type of mutations has been largely understudied, and their role in the disease remains largely unknown (see Creixell et al., 2015).

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).


Unmasking determinants of specificity in the human kinome.

Creixell P, Palmeri A, Miller CJ, Lou HJ, Santini CC, Nielsen M, Turk BE, Linding R - Cell (2015)

Model for DoS Encoding Specificity and Mutations on DoS Perturbing Substrate Specificity(A) By computing the percentage of residues encoding specificity (DoS) and their average distance to the substrate, we conclude that the set of DoS uncovered by KINspect represent a larger and more sparse group of residues and that residues can contribute to peptide specificity even if they are not located in close proximity to the substrate.(B) In this article, we have described the degree to which each residue contribute to specificity on a more quantitative scale and experimentally validated three novel determinants of specificity (Figure 3). Our results also indicate that specificity is loaded onto a set of residues that is less conserved than most others in the domain and where mutations, in cancer or evolution, can easily cause substrate specificity switches by single mutations. As shown in similar signaling systems (Skerker et al., 2008), such mutations represent key turns in how different kinases evolve and occupy separate and sometimes overlapping substrate subspaces. Similar mutations have been seen in cancer (Borrello et al., 1995, Creixell et al., 2012, Santoro et al., 1995, Songyang et al., 1995), despite the fact that this type of mutations has been largely understudied, and their role in the disease remains largely unknown (see Creixell et al., 2015).
© Copyright Policy - CC BY
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4644237&req=5

fig7: Model for DoS Encoding Specificity and Mutations on DoS Perturbing Substrate Specificity(A) By computing the percentage of residues encoding specificity (DoS) and their average distance to the substrate, we conclude that the set of DoS uncovered by KINspect represent a larger and more sparse group of residues and that residues can contribute to peptide specificity even if they are not located in close proximity to the substrate.(B) In this article, we have described the degree to which each residue contribute to specificity on a more quantitative scale and experimentally validated three novel determinants of specificity (Figure 3). Our results also indicate that specificity is loaded onto a set of residues that is less conserved than most others in the domain and where mutations, in cancer or evolution, can easily cause substrate specificity switches by single mutations. As shown in similar signaling systems (Skerker et al., 2008), such mutations represent key turns in how different kinases evolve and occupy separate and sometimes overlapping substrate subspaces. Similar mutations have been seen in cancer (Borrello et al., 1995, Creixell et al., 2012, Santoro et al., 1995, Songyang et al., 1995), despite the fact that this type of mutations has been largely understudied, and their role in the disease remains largely unknown (see Creixell et al., 2015).
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).

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.

View Article: PubMed Central - PubMed

Affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark. Electronic address: creixell@mit.edu.

Show MeSH
Related in: MedlinePlus