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Phosphosite Scanning reveals a complex phosphorylation code underlying CDK-dependent activation of Hcm1

Conti, Michelle M
Li, Rui
Narváez Ramos, Michelle A
Zhu, Lihua Julie
Fazzio, Thomas G
Benanti, Jennifer A
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Abstract

Ordered cell cycle progression is coordinated by cyclin dependent kinases (CDKs). CDKs often phosphorylate substrates at multiple sites clustered within disordered regions. However, for most substrates, it is not known which phosphosites are functionally important. We developed a high-throughput approach, Phosphosite Scanning, that tests the importance of each phosphosite within a multisite phosphorylated domain. We show that Phosphosite Scanning identifies multiple combinations of phosphosites that can regulate protein function and reveals specific phosphorylations that are required for phosphorylation at additional sites within a domain. We applied this approach to the yeast transcription factor Hcm1, a conserved regulator of mitotic genes that is critical for accurate chromosome segregation. Phosphosite Scanning revealed a complex CDK-regulatory circuit that mediates Cks1-dependent phosphorylation of key activating sites in vivo. These results illuminate the mechanism of Hcm1 activation by CDK and establish Phosphosite Scanning as a powerful tool for decoding multisite phosphorylated domains.

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Conti MM, Li R, Narváez Ramos MA, Zhu LJ, Fazzio TG, Benanti JA. Phosphosite Scanning reveals a complex phosphorylation code underlying CDK-dependent activation of Hcm1. Nat Commun. 2023 Jan 19;14(1):310. doi: 10.1038/s41467-023-36035-9. PMID: 36658165; PMCID: PMC9852432.

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10.1038/s41467-023-36035-9
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36658165
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Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/. © The Author(s) 2023Attribution 4.0 International