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Unveiling the Complexity of cis-Regulation Mechanisms in Kinases: A Comprehensive Analysis
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  • Alvaro M. Navarro,
  • Macarena Alonso,
  • Elizabeth Martínez-Pérez,
  • Tamas Lazar,
  • Toby J. Gibson,
  • Javier A. Iserte,
  • Peter Tompa,
  • Cristina Marino-Buslje
Alvaro M. Navarro
Fundacion Instituto Leloir
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Macarena Alonso
Fundacion Instituto Leloir
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Elizabeth Martínez-Pérez
Fundacion Instituto Leloir
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Tamas Lazar
VIB-VUB Center for Structural Biology Flanders Institute for Biotechnology (VIB
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Toby J. Gibson
European Molecular Biology Laboratory
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Javier A. Iserte
Fundacion Instituto Leloir
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Peter Tompa
VIB-VUB Center for Structural Biology Flanders Institute for Biotechnology (VIB
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Cristina Marino-Buslje
Fundacion Instituto Leloir

Corresponding Author:cmb@leloir.org.ar

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Abstract

Protein cis-regulatory elements (CREs) are regions that modulate the activity of a protein through intramolecular interactions. Kinases, pivotal enzymes in numerous biological processes, often undergo regulatory control via inhibitory interactions in cis. This study delves into the mechanisms of cis regulation in kinases mediated by CREs, employing a combined structural and sequence analysis. To accomplish this, we curated an extensive dataset of kinases featuring annotated CREs, organized into homolog families through multiple sequence alignments. Key molecular attributes, including disorder and secondary structure content, active and ATP-binding sites, post-translational modifications, and disease-associated mutations, were systematically mapped onto all sequences. Additionally, we explored the potential for conformational changes between active and inactive states. Finally, we explored the presence of these kinases within membraneless organelles and elucidated their functional roles therein. CREs display a continuum of structures, ranging from short disordered stretches to fully folded domains. The adaptability demonstrated by CREs in achieving the common goal of kinase inhibition spans from direct autoinhibitory interaction with the active site within the kinase domain, to CREs binding to an alternative site, inducing allosteric regulation revealing distinct types of inhibitory mechanisms, which we exemplify by archetypical representative systems. While this study provides a systematic approach to comprehend kinase CREs, further experimental investigations are imperative to unravel the complexity within distinct kinase families. The insights gleaned from this research lay the foundation for future studies aiming to decipher the molecular basis of kinase dysregulation, and explore potential therapeutic interventions.
24 Apr 2024Submitted to PROTEINS: Structure, Function, and Bioinformatics
27 Apr 2024Submission Checks Completed
27 Apr 2024Assigned to Editor
27 Apr 2024Review(s) Completed, Editorial Evaluation Pending
13 Aug 2024Editorial Decision: Revise Minor
22 Aug 20241st Revision Received
30 Aug 2024Submission Checks Completed
30 Aug 2024Assigned to Editor
30 Aug 2024Review(s) Completed, Editorial Evaluation Pending
05 Sep 2024Reviewer(s) Assigned
12 Sep 2024Editorial Decision: Accept