Emergence and evolution of an interaction between intrinsically disordered proteins

Area of Science:

• Evolutionary biology
• Molecular biology
• Biophysics

Background:

• Protein-protein interactions involving intrinsically disordered proteins (IDPs) are crucial for cellular functions across all organisms.
• The molecular mechanisms underlying the emergence and evolution of these interactions remain largely unknown.

Purpose of the Study:

• To investigate the evolutionary trajectory of protein-protein interactions involving intrinsically disordered protein domains.
• To elucidate the molecular basis for the evolution of interaction affinity and specificity.

Main Methods:

• Phylogenetic reconstruction and ancestral protein resurrection of two interacting disordered domains, CID and NCBD.
• Biophysical characterization of ancient and modern CID/NCBD complexes using techniques like NMR.
• Molecular modeling to understand the role of dynamics and mutations in interaction evolution.

Main Results:

• The NCBD domain predates the protostome/deuterostome ancestor, while the CID domain emerged later, approximately 450-600 million years ago.
• The earliest CID/NCBD complex exhibited weak binding affinity (Kd ~5 µM), which significantly increased to ~200 nM after the vertebrate-specific genome duplication.
• This enhanced affinity was conserved throughout subsequent speciation, suggesting a stable evolutionary adaptation.

Conclusions:

• New interactions involving intrinsically disordered proteins may originate from low-affinity complexes.
• Evolutionary optimization involves modulating direct interactions and dynamics, while tolerating potentially disruptive mutations.
• This provides a framework for understanding how complex protein interaction networks evolve from simpler precursors.