Signaling pathways and disordered proteins

This 2022 review explored the title subject:

“Cell signaling imposes many demands on proteins that comprise these pathways, including abilities to form active and inactive states, and to engage in multiple protein interactions. Signaling often requires amplifying signals, regulating or tuning responses to signals, combining information sourced from multiple pathways, all while ensuring process fidelity.

Sensitivity, adaptability, and tunability are possible, in part, due to inclusion of intrinsically disordered regions in many proteins involved in cell signaling.  This review highlights the critical role of intrinsically disordered proteins for signaling:

  • In widely diverse organisms (animals, plants, bacteria, fungi);
  • In every category of cell signaling pathway (autocrine, juxtacrine, intracrine, paracrine, and endocrine); and
  • At each stage (ligand, receptor, transducer, effector, terminator) in the cell signaling process.

Function of the glucocorticoid receptor is regulated in part by its intrinsically disordered C-terminal tail. Prior to activation, the glucocorticoid receptor resides in cytosol:

glucocorticoid receptor

Intrinsic disorder in the glucocorticoid receptor not only enables multiple allosteric regulatory interactions to impact function, but also allows deployment of different surfaces of the protein to enable binding to many different sets of macromolecules, and regulation of these interactions via mRNA splicing and phosphorylation.

Combinations of alternative translation initiation and alternative mRNA splicing result in production of multiple glucocorticoid receptor isoforms from one gene. Various isoforms exhibit distinctive tissue distribution patterns and altered transcriptional regulatory profiles.

Greater than 90% of transcription factors either contain intrinsically disordered regions of proteins or are entirely intrinsically disordered. The many advantages conferred by disorder to cell signaling cascades means that:

  1. Understanding signaling required definition of roles disorder plays in each pathway;
  2. Many more examples of disordered proteins in cell signaling pathways are likely to be discovered; and
  3. More mechanisms by which disorder functions remain to be elucidated.”

https://biosignaling.biomedcentral.com/articles/10.1186/s12964-022-00821-7 “Intrinsically disordered proteins play diverse roles in cell signaling”


Cells in vivo seldom act on their own impetus. I would have liked discussion – or at least mention – of bidirectional signals between genes / cells / tissues / organs / organism / environment. This review’s topic of cell signaling pathways excluded “interactions of complex, interconnected systems spanning hierarchical levels” as explored in An environmental signaling paradigm of aging.

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