An atlas of substrate specificities for the human serine/threonine kinome. Johnson, J. L., Yaron, T. M., Huntsman, E. M., Kerelsky, A., Song, J., Regev, A., Lin, T., Liberatore, K., Cizin, D. M., Cohen, B. M., Vasan, N., Ma, Y., Krismer, K., Robles, J. T., van de Kooij, B., van Vlimmeren, A. E., Andrée-Busch, N., Käufer, N. F., Dorovkov, M. V., Ryazanov, A. G., Takagi, Y., Kastenhuber, E. R., Goncalves, M. D., Hopkins, B. D., Elemento, O., Taatjes, D. J., Maucuer, A., Yamashita, A., Degterev, A., Uduman, M., Lu, J., Landry, S. D., Zhang, B., Cossentino, I., Linding, R., Blenis, J., Hornbeck, P. V., Turk, B. E., Yaffe, M. B., & Cantley, L. C. Nature, 613(7945):759–766, January, 2023. Number: 7945 Publisher: Nature Publishing Group
An atlas of substrate specificities for the human serine/threonine kinome [link]Paper  doi  abstract   bibtex   
Protein phosphorylation is one of the most widespread post-translational modifications in biology1,2. With advances in mass-spectrometry-based phosphoproteomics, 90,000 sites of serine and threonine phosphorylation have so far been identified, and several thousand have been associated with human diseases and biological processes3,4. For the vast majority of phosphorylation events, it is not yet known which of the more than 300 protein serine/threonine (Ser/Thr) kinases encoded in the human genome are responsible3. Here we used synthetic peptide libraries to profile the substrate sequence specificity of 303 Ser/Thr kinases, comprising more than 84% of those predicted to be active in humans. Viewed in its entirety, the substrate specificity of the kinome was substantially more diverse than expected and was driven extensively by negative selectivity. We used our kinome-wide dataset to computationally annotate and identify the kinases capable of phosphorylating every reported phosphorylation site in the human Ser/Thr phosphoproteome. For the small minority of phosphosites for which the putative protein kinases involved have been previously reported, our predictions were in excellent agreement. When this approach was applied to examine the signalling response of tissues and cell lines to hormones, growth factors, targeted inhibitors and environmental or genetic perturbations, it revealed unexpected insights into pathway complexity and compensation. Overall, these studies reveal the intrinsic substrate specificity of the human Ser/Thr kinome, illuminate cellular signalling responses and provide a resource to link phosphorylation events to biological pathways.
@article{johnson_atlas_2023,
	title = {An atlas of substrate specificities for the human serine/threonine kinome},
	volume = {613},
	copyright = {2023 The Author(s)},
	issn = {1476-4687},
	url = {https://www.nature.com/articles/s41586-022-05575-3},
	doi = {10.1038/s41586-022-05575-3},
	abstract = {Protein phosphorylation is one of the most widespread post-translational modifications in biology1,2. With advances in mass-spectrometry-based phosphoproteomics, 90,000 sites of serine and threonine phosphorylation have so far been identified, and several thousand have been associated with human diseases and biological processes3,4. For the vast majority of phosphorylation events, it is not yet known which of the more than 300 protein serine/threonine (Ser/Thr) kinases encoded in the human genome are responsible3. Here we used synthetic peptide libraries to profile the substrate sequence specificity of 303 Ser/Thr kinases, comprising more than 84\% of those predicted to be active in humans. Viewed in its entirety, the substrate specificity of the kinome was substantially more diverse than expected and was driven extensively by negative selectivity. We used our kinome-wide dataset to computationally annotate and identify the kinases capable of phosphorylating every reported phosphorylation site in the human Ser/Thr phosphoproteome. For the small minority of phosphosites for which the putative protein kinases involved have been previously reported, our predictions were in excellent agreement. When this approach was applied to examine the signalling response of tissues and cell lines to hormones, growth factors, targeted inhibitors and environmental or genetic perturbations, it revealed unexpected insights into pathway complexity and compensation. Overall, these studies reveal the intrinsic substrate specificity of the human Ser/Thr kinome, illuminate cellular signalling responses and provide a resource to link phosphorylation events to biological pathways.},
	language = {en},
	number = {7945},
	urldate = {2023-03-02},
	journal = {Nature},
	author = {Johnson, Jared L. and Yaron, Tomer M. and Huntsman, Emily M. and Kerelsky, Alexander and Song, Junho and Regev, Amit and Lin, Ting-Yu and Liberatore, Katarina and Cizin, Daniel M. and Cohen, Benjamin M. and Vasan, Neil and Ma, Yilun and Krismer, Konstantin and Robles, Jaylissa Torres and van de Kooij, Bert and van Vlimmeren, Anne E. and Andrée-Busch, Nicole and Käufer, Norbert F. and Dorovkov, Maxim V. and Ryazanov, Alexey G. and Takagi, Yuichiro and Kastenhuber, Edward R. and Goncalves, Marcus D. and Hopkins, Benjamin D. and Elemento, Olivier and Taatjes, Dylan J. and Maucuer, Alexandre and Yamashita, Akio and Degterev, Alexei and Uduman, Mohamed and Lu, Jingyi and Landry, Sean D. and Zhang, Bin and Cossentino, Ian and Linding, Rune and Blenis, John and Hornbeck, Peter V. and Turk, Benjamin E. and Yaffe, Michael B. and Cantley, Lewis C.},
	month = jan,
	year = {2023},
	note = {Number: 7945
Publisher: Nature Publishing Group},
	keywords = {Bioinformatics, Cellular signalling networks, Kinases, Phosphorylation},
	pages = {759--766},
}
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