Extreme disorder in an ultrahigh-affinity protein complex.

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Protein interactions mediate molecular communication in biology.
• Current understanding emphasizes specific binding interfaces for interaction specificity and affinity.
• Intrinsically disordered proteins often interact with structured binding sites.

Purpose of the Study:

• To investigate an unexpected protein interaction mechanism.
• To characterize the interaction between intrinsically disordered human proteins histone H1 and prothymosin-α.
• To determine the basis of high-affinity binding between these disordered proteins.

Main Methods:

• Integrated experimental approaches.
• Molecular simulations.
• Proteome-wide sequence analysis.

Main Results:

• Histone H1 and prothymosin-α form a complex with picomolar affinity.
• Both proteins retain their structural disorder, flexibility, and dynamic character upon binding.
• The interaction is driven by large opposite net charges, not specific residue interactions or defined binding sites.

Conclusions:

• A novel mechanism for high-affinity protein-protein interactions involving intrinsically disordered proteins has been identified.
• This charge-based interaction mechanism challenges the traditional paradigm of binding interface complementarity.
• The findings suggest that such charge-driven interactions may be prevalent in eukaryotic proteomes.