Beyond the structure-function paradigm: A comprehensive review of intrinsically disordered proteins

Area of Science:

• Biochemistry and Molecular Biology
• Genetics and Genomics
• Cell Biology

Background:

• Intrinsically disordered proteins (IDPs) and regions (IDRs) are crucial for cellular processes despite lacking fixed structures.
• Their dynamic nature allows for versatile interactions, signaling, and organization, challenging traditional protein structure-function paradigms.
• IDPs play key roles in chromatin regulation, transcriptional control, and the formation of membrane-less organelles via liquid-liquid phase separation (LLPS).

Purpose of the Study:

• To synthesize a cross-kingdom understanding of disorder-based chromatin regulation.
• To integrate diverse disease pathways linked to IDP conformational dysregulation.
• To explore novel regulatory mechanisms and evaluate advanced characterization techniques for IDPs.

Main Methods:

• Cross-kingdom comparative analysis of chromatin regulation mechanisms.
• Integration of disparate disease pathways (mitophagy, oxidative stress, neuroinflammation, phase separation).
• Review of emerging IDP regulatory dimensions (proline isomerization, ubiquitylation) and computational/experimental characterization methods.

Main Results:

• A conserved charge-regulatory logic mediated by PTMs links environmental signals to genome organization across kingdoms.
• A unified framework connects IDP dysregulation to neurodegeneration and cancer through pathways like aberrant phase separation.
• New regulatory insights from proline isomerization and ubiquitylation, alongside AI-driven prediction and ensemble characterization.

Conclusions:

• IDP conformational plasticity is central to biological regulation and disease.
• Targeting IDPs presents therapeutic opportunities for neurodegeneration, cancer, and other pathologies.
• Advanced computational and experimental approaches are essential for understanding and targeting these dynamic proteins.