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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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Related to Figure 6(A) Alpha Determination for SH2 KINspect. Similarly as in Figure S2, an optimal parameter ‘alpha’ (α) needed to be set for KINspect when deployed on the SH2 dataset. As shown here, in this case, the best-performing value is α = 7, so this value was used subsequently.(B) Fitness Evolution for SH2 KINspect. As observed in Figure S2 for the kinase domain, fitness evolutions and convergences are similar for the ten different evaluation runs of SH2 KINspect.(C) SH2 Specificity Masks Similarity Over the Different Generations. Similarly as in Figure S2 for the kinase domain, an increase in similarity among specificity masks between different evaluation runs is observed as we move closer to the end of the KINspect optimization, suggesting different evaluation runs converge approximately to the same solution.
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figs6: Related to Figure 6(A) Alpha Determination for SH2 KINspect. Similarly as in Figure S2, an optimal parameter ‘alpha’ (α) needed to be set for KINspect when deployed on the SH2 dataset. As shown here, in this case, the best-performing value is α = 7, so this value was used subsequently.(B) Fitness Evolution for SH2 KINspect. As observed in Figure S2 for the kinase domain, fitness evolutions and convergences are similar for the ten different evaluation runs of SH2 KINspect.(C) SH2 Specificity Masks Similarity Over the Different Generations. Similarly as in Figure S2 for the kinase domain, an increase in similarity among specificity masks between different evaluation runs is observed as we move closer to the end of the KINspect optimization, suggesting different evaluation runs converge approximately to the same solution.

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).


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)

Related to Figure 6(A) Alpha Determination for SH2 KINspect. Similarly as in Figure S2, an optimal parameter ‘alpha’ (α) needed to be set for KINspect when deployed on the SH2 dataset. As shown here, in this case, the best-performing value is α = 7, so this value was used subsequently.(B) Fitness Evolution for SH2 KINspect. As observed in Figure S2 for the kinase domain, fitness evolutions and convergences are similar for the ten different evaluation runs of SH2 KINspect.(C) SH2 Specificity Masks Similarity Over the Different Generations. Similarly as in Figure S2 for the kinase domain, an increase in similarity among specificity masks between different evaluation runs is observed as we move closer to the end of the KINspect optimization, suggesting different evaluation runs converge approximately to the same solution.
© Copyright Policy - CC BY
Related In: Results  -  Collection

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

figs6: Related to Figure 6(A) Alpha Determination for SH2 KINspect. Similarly as in Figure S2, an optimal parameter ‘alpha’ (α) needed to be set for KINspect when deployed on the SH2 dataset. As shown here, in this case, the best-performing value is α = 7, so this value was used subsequently.(B) Fitness Evolution for SH2 KINspect. As observed in Figure S2 for the kinase domain, fitness evolutions and convergences are similar for the ten different evaluation runs of SH2 KINspect.(C) SH2 Specificity Masks Similarity Over the Different Generations. Similarly as in Figure S2 for the kinase domain, an increase in similarity among specificity masks between different evaluation runs is observed as we move closer to the end of the KINspect optimization, suggesting different evaluation runs converge approximately to the same solution.
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).

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