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ORIGINAL RESEARCH article

Front. Mol. Biosci.

Sec. Protein Biochemistry for Basic and Applied Sciences

Volume 12 - 2025 | doi: 10.3389/fmolb.2025.1557835

Positional distribution and conservation of major Phosphorylated sites in the Human Kinome

Provisionally accepted
Athira P G Athira P G 1,2Prathik Basthikoppa Shivamurthy Prathik Basthikoppa Shivamurthy 1Dr. Mukhtar Ahmed Dr. Mukhtar Ahmed 3Samseera Ummar Samseera Ummar 1Poornima Ramesh Poornima Ramesh 1Sonet Daniel Thomas Sonet Daniel Thomas 1,2Althaf Mahin Althaf Mahin 1,2Mahammad Nisar Mahammad Nisar 1Sowmya Soman Sowmya Soman 1Yashwanth Subbannayya Yashwanth Subbannayya 4Rajesh Raju Rajesh Raju 1,2*
  • 1 Centre for Integrative Omics Data Science, Yenepoya Mangalore, India
  • 2 Center for Systems Biology and Molecular Medicine, Yenepoya University, Mangalore, Karnataka, India
  • 3 Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
  • 4 School of Biosciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, England, United Kingdom

The final, formatted version of the article will be published soon.

    The human protein kinome is a group of over 500 therapeutically relevant kinases. Exemplified by over 10,000 phosphorylated sites reported in global phosphoproteomes, kinases are also highly regulated by phosphorylation. Currently, 1008 phosphorylated sites in 273 kinases are associated with their regulation of activation/inhibition, and a few in 30 kinases are associated with altered activity. Phosphorylated sites in 196 kinases are related to other molecular functions such as localization and protein interactions. Over 8000 phosphorylated sites, including all those in 517 kinases are unassigned to any functions. This imposes a significant bias and challenge for the effective analysis of global phosphoproteomics datasets. Hence, we derived a set of stably and frequently detected phosphorylated sites (representative phosphorylated sites) across diverse experimental conditions annotated in the PhosphoSitePlus database and presumed them to be relevant to the human kinase regulatory network. Analysis of these representative phosphorylated sites led to the classification of 449 kinases into 4 distinct categories (kinases with phosphorylated sites apportioned (PaKD) and enigmatic (PeKD), and those with predominantly within kinase domain (PiKD) and outside kinase domain (PoKD)). Knowledge-based functional analysis and sequence conservation across the family/subfamily identified phosphorylated sites unique to specific kinases that could contribute to their unique functions. This classification of representative kinase phosphorylated sites enhance our understanding of prioritized validation and provides a novel framework for targeted phosphorylated site enrichment approaches. Phosphorylated sites in kinases associated with dysregulation in diseases were frequently located outside the kinase domain, and suggesting their regulatory roles and opportunities for phosphorylated site-directed therapeutic approaches.

    Keywords: Predominant phosphorylated sites, Kinome classification, Kinase domain, kinase family, Functional phosphorylated sites

    Received: 09 Jan 2025; Accepted: 27 Mar 2025.

    Copyright: © 2025 P G, Shivamurthy, Ahmed, Ummar, Ramesh, Thomas, Mahin, Nisar, Soman, Subbannayya and Raju. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Rajesh Raju, Centre for Integrative Omics Data Science, Yenepoya Mangalore, 575018, India

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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