Intrinsically Disordered Protein Regions (IDR) function outside of Neo-Darwinism

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Review Article

The molecular basis for cellular function of intrinsically disordered protein regions

Published: 13 November 2023, Nature Reviews

Intrinsically disordered proteins (IDPs) are a diverse and fascinating class of proteins that lack a stable three-dimensional structure under physiological conditions. Despite their lack of a defined structure, IDPs play crucial roles in a wide variety of cellular processes, including signal transduction, transcription, translation, and cell regulation. In recent years, the study of IDPs has gained significant traction, revealing their multifaceted contributions to cellular function and their potential as therapeutic targets.

Structural Properties and Dynamic Conformations

Unlike structured proteins, which adopt a defined three-dimensional shape, IDPs exhibit a dynamic and flexible nature. Their amino acid sequences are enriched in hydrophilic and charged residues, which favor a lack of stable intramolecular interactions and promote structural heterogeneity. This inherent flexibility allows IDPs to transition between a myriad of conformations, enabling them to adapt to their environment and interact with diverse binding partners. As well they can tolerate mutations over billions of years maintaining their function. No evolution for billions of year's. Some scientists think this explains “living fossils.”


Functional Roles of IDPs in Cellular Processes

IDPs play pivotal roles in various cellular processes, often acting as hubs or scaffolds that orchestrate complex molecular interactions. Their dynamic nature allows them to transiently bind to multiple partners, modulating their activity and function. This ability to form transient interactions is essential for processes such as signal transduction, where IDPs relay signals from the cell's exterior to the interior, triggering downstream signaling cascades.

In transcription, IDPs act as regulatory elements, influencing gene expression by interacting with DNA and transcription factors. Their ability to adopt different conformations allows them to modulate the accessibility of DNA-binding sites and control the assembly of transcription complexes. This violates the Central Dogma which says information can not go from proteins to DNA. 


IDPs also play important roles in translation, facilitating the initiation, elongation, and termination of protein synthesis. Their flexible structures allow them to interact with ribosomes and translation factors, ensuring the accurate and efficient production of proteins.

IDPs as Potential Therapeutic Targets

The unique structural and functional properties of IDPs have opened new avenues for therapeutic development. Due to their dynamic nature, IDPs are often considered "undruggable" targets using traditional small-molecule inhibitors. However, recent advances in drug discovery have led to the development of novel therapeutic strategies targeting IDPs.

One approach involves the use of peptide-based inhibitors that mimic the natural binding partners of IDPs, disrupting their interactions and modulating their function. Another strategy involves targeting the post-translational modifications of IDPs, as these modifications can alter their structure and activity. Additionally, the development of computational methods and biophysical techniques has facilitated the identification and characterization of IDPs, providing valuable insights for drug discovery efforts.

Conclusion

The study of IDPs has revolutionized our understanding of protein function and their roles in cellular processes. Their dynamic and flexible nature allows them to adapt to their environment and interact with diverse binding partners, playing crucial roles in signal transduction, transcription, translation, and cell regulation. As research continues to shed light on the intricacies of IDPs, their potential as therapeutic targets for various diseases is becoming increasingly evident.

The implication of the article  challenges neo-Darwinism in several ways.

  1. Intrinsically disordered protein regions (IDRs) are a large and diverse group of proteins that do not have a stable three-dimensional structure. This is in contrast to the traditional model of protein structure, which holds that proteins fold into a specific three-dimensional shape in order to function. 

NeoDarwinism was founded on this idea. A mutation in principle can change this structure and be selected for.


The existence of IDRs suggests that the traditional model of protein structure is not always accurate, and that proteins can function without having a stable three-dimensional structure.

  1. IDRs are often involved in important cellular processes, such as signal transduction, transcription regulation, and cell division. This suggests that IDRs are not simply evolutionary relics, but are instead essential components of the cellular machinery.

  2. IDRs are often highly flexible and can change their shape in response to changes in their environment. This suggests that IDRs may play a role in regulating cellular processes by responding to environmental cues.

  3. IDRs are often involved in protein-protein interactions. This suggests that IDRs may play a role in mediating cellular communication by providing a scaffold for protein-protein interactions to occur.

  4. IDRs are often involved in post-translational modifications, such as phosphorylation and methylation (epigenetics). This suggests that IDRs may be regulated by post-translational modifications, which could provide another layer of control over cellular processes.

Overall, the existence of IDRs and their involvement in important cellular processes challenges neo-Darwinism by suggesting that proteins can function without having a stable three-dimensional structure, that IDRs are essential components of the cellular machinery, and that IDRs may play a role in regulating cellular processes by responding to environmental cues. These findings suggest that the traditional NeoDarwinian model of protein structure and function needs to be revised if not replaced to accommodate the existence of IDRs.

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