Phosphorylation regulates the binding of intrinsically disordered proteins via a flexible conformation selection...

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biophysics

Background:

• Phosphorylation is a key post-translational modification regulating protein function.
• The kinase-inducible domain (KID), an intrinsically disordered protein (IDP), undergoes phosphorylation to bind the KIX domain.
• The precise regulatory mechanism of phosphorylation on KID's binding and folding remains unclear.

Purpose of the Study:

• To elucidate the structural ensembles and binding mechanism of phosphorylated KID (pKID) with the KIX domain.
• To investigate the role of phosphorylation in promoting the folding and interaction of IDPs.
• To propose a model for the binding and folding process of IDPs.

Main Methods:

• All-atom enhanced sampling simulations were employed to study pKID-KIX interactions.
• Analysis of structural ensembles and dynamic interactions.
• Investigating the formation of hydrophobic interactions and residue clusters.

Main Results:

• Phosphorylation increases hydrophobic interactions within pKID, facilitating the formation of a hydrophobic residue cluster (HRC).
• The pre-formed HRC in pKID promotes specific binding to KIX and subsequent pKID folding.
• A flexible conformational selection model accurately describes the binding and folding dynamics.

Conclusions:

• Phosphorylation-driven hydrophobic interactions are crucial for the specific binding and folding of IDPs.
• The proposed conformational selection model provides new insights into IDP regulation by phosphorylation.
• Understanding these dynamic interactions is vital for protein regulation studies.