Disordered but Different: Functional and Evolutionary Divergence of Transcription Factor Intrinsically Disordered...

Area of Science:

• Proteomics
• Evolutionary Biology
• Molecular Biology

Background:

• Intrinsically disordered regions (IDRs) are crucial for protein functions like multivalent interactions and biomolecular condensate formation.
• IDRs are prevalent in the human proteome, particularly in transcription factor (TF) activation domains.

Purpose of the Study:

• To investigate the evolutionary dynamics of protein disorder.
• To determine if TF IDRs differ systematically from non-TF IDRs.

Main Methods:

• Comprehensive identification and analysis of IDRs across the human proteome.
• Comparative analysis of TF and non-TF IDRs.

Main Results:

• TF and non-TF IDRs show significant functional, phenotypic, and evolutionary differences.
• TFs have progressively evolved to be more disordered, unlike the broader proteome.
• Highly disordered TFs are linked to developmental processes, larger regulatory networks, and stronger regulatory constraints.
• TF IDRs are enriched for pathogenic mutations, and disorder content predicts disease inheritance patterns.

Conclusions:

• The evolution of gene regulation has uniquely shaped TF IDRs' molecular function and disease association.
• Disorder in TFs plays a critical role in their regulatory roles and disease susceptibility.