The unfoldomics decade: an update on intrinsically disordered proteins.

Area of Science:

• Biochemistry
• Bioinformatics
• Molecular Biology

Background:

• Protein disorder prediction has evolved significantly over the past decade, with numerous research groups contributing to improved methodologies.
• While protein disorder prediction methods share similarities with secondary structure prediction, the underlying protein structures and dynamics are fundamentally different.
• The concept of intrinsic protein disorder has revolutionized the understanding of protein structure-function relationships, challenging traditional views.

Purpose of the Study:

• To review key discoveries in protein disorder and integrate them into novel frameworks for understanding sequence-function relationships.
• To highlight the widespread prevalence and functional significance of intrinsically disordered proteins across all domains of life.

Main Methods:

• Review of existing literature and experimental evidence on protein disorder.
• Bioinformatic analysis of genome-wide predictions of intrinsic disorder.
• Examination of disease-associated proteins and their relation to intrinsic disorder.

Main Results:

• Intrinsically disordered proteins are prevalent across all three domains of life, particularly in eukaryotes.
• Many significant biological functions are intrinsically linked to the unfolded or partially folded states of proteins.
• Signaling sequences and post-translational modification sites are frequently located within intrinsically disordered regions.

Conclusions:

• Disorder-to-order transitions facilitate diverse binding interactions, crucial for protein-protein networks and gene regulation.
• The interplay of disorder and alternative splicing in eukaryotes drives signaling diversity, cell differentiation, and multicellularity.
• Targeting protein-protein interactions involving intrinsically disordered proteins presents a promising new avenue for drug discovery, particularly for disease-associated proteins.