Structured States of Disordered Proteins from Genomic Sequences

Area of Science:

• Biochemistry
• Structural Biology
• Genomics

Background:

• Protein flexibility spans from simple movements to functional disorder.
• Approximately 50% of human proteins contain disordered regions, often linked to disease.
• Predicting 3D states of ordered proteins and RNA has been achieved using evolutionary couplings.

Purpose of the Study:

• To develop a method for predicting ordered states in apparently disordered proteins.
• To assess the structural potential of over 1,000 disordered regions in human proteins.
• To uncover previously unknown functional structures within disordered proteins.

Main Methods:

• Adapted the evolutionary couplings approach for disordered protein analysis.
• Applied the method to predict residue interactions in known disordered regions.
• Evaluated accuracy using over 60 experimentally characterized disordered regions.

Main Results:

• The developed method accurately predicts residue interactions (79%) in disordered regions.
• At least 50% of assessed disordered regions show a propensity for forming 2D or 3D structures.
• Co-evolutionary constraints revealed significant, previously unrecognized structures.

Conclusions:

• Intrinsically disordered proteins possess a continuum of structural order.
• The method successfully predicts structure in disordered proteins, offering new functional insights.
• This approach advances our understanding of protein structure-disease relationships.