Unveiling the Complexity of cis-Regulation Mechanisms in Kinases: A
Comprehensive Analysis
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.