Electrostatically accelerated coupled binding and folding of intrinsically disordered proteins

Area of Science:

• Biochemistry
• Structural Biology
• Biophysics

Background:

• Intrinsically disordered proteins (IDPs) are crucial in biological processes but face kinetic challenges due to folding requirements.
• Despite this, IDPs often bind targets as rapidly as structured proteins, suggesting efficient recognition mechanisms.

Purpose of the Study:

• To investigate how intrinsically disordered proteins achieve efficient folding upon encounter for rapid recognition.
• To elucidate the role of electrostatic and hydrophobic interactions in IDP binding kinetics using p27(Kip1) as a model.

Main Methods:

• Experimental techniques combined with coarse-grained modeling.
• Analysis of electrostatic and hydrophobic interactions in IDP-protein complexes.

Main Results:

• Long-range electrostatic interactions between p27 and cyclin A accelerate encounter rates and promote folding-competent states.
• Nonspecific hydrophobic interactions can hinder folding efficiency and slow down binding kinetics.
• IDP binding sites are often hydrophobic, but their surroundings are frequently charge-enriched to complement IDPs.

Conclusions:

• Electrostatically accelerated encounter and induced folding are likely prevalent mechanisms for facile IDP recognition.
• This mechanism helps overcome kinetic bottlenecks associated with IDP binding.