Bimodal evolution of Src and Abl kinase substrate specificity revealed using mammalian cell extract as substrate pool
Finneran, P.; Soucheray, M.; Wilson, C.; Otten, R.; Buosi, V.; Krogan, N. J.; Swaney, D.; Theobald, D.; Kern, D.
Show abstract
The specificity of phosphorylation by protein kinases is essential to the integrity of biological signal transduction. While peptide sequence specificity for individual kinases has been examined previously, here we explore the evolutionary progression that has led to the modern substrate specificity of two non-receptor tyrosine kinases, Abl and Src. To efficiently determine the substrate specificity of modern and reconstructed ancestral kinases, we developed a method using mammalian cell lysate as the substrate pool, thereby representing the naturally occurring substrate proteins. We find that the oldest tyrosine kinase ancestor was a promiscuous enzyme that evolved through a more specific last common ancestor into a specific human Abl. In contrast, the parallel pathway to human Src involved a loss of substrate specificity, leading to general promiscuity. These results add a new facet to our understanding of the evolution of signaling pathways, with both subfunctionalization and neofunctionalization along the evolutionary trajectories.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Allosteric Regulation of the EphA2 Receptor Intracellular Region by Serine/Threonine Kinases 96%
- Feed-forward stimulation of CAMK2 by the oncogenic pseudokinase PEAK1 generates a therapeutically "actionable" signalling axis in triple negative breast cancer 95%
- Juxtaposition of Bub1 and Cdc20 on phosphorylated Mad1 during catalytic mitotic checkpoint complex assembly 95%
Similar papers in this journal
Similar papers in this journal
Similar papers in this journal
- Mechanism and evolutionary origins of Alanine-tail C-degron recognition by E3 ligases Pirh2 and CRL2-KLHDC10 94%
- NEMO recruitment at single cytokine-receptor complexes shows quantized dynamics independent of ligand affinity 94%
- Distinct interactions stabilize EGFR dimers and higher-order oligomers in cell membranes 94%
Similar papers in this journal
- Controlled protein activities with viral proteases, antiviral peptides, and antiviral drugs 93%
- Recognition of histone H3 methylation states by the PHD1 domain of histone demethylase KDM5A 93%
- Novel substrate prediction for the TAM family of RTKs using phosphoproteomics and structure-based modeling 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.