Functional interplay between protein domains in a supramodular structure involving the postsynaptic density protein...

Area of Science:

• Molecular and Cellular Biology
• Structural Biology
• Biophysics

Background:

• Protein-protein interactions are crucial for cell scaffolding and signaling.
• Multidomain proteins often exhibit complex interactions modulated by adjacent domains and supertertiary structures.
• The postsynaptic density protein 95 (PSD-95) supramodule (PSG) involves PDZ, SH3, and guanylate kinase-like domains.

Purpose of the Study:

• To investigate the binding kinetics of the PSG supramodule with its ligand CRIPT.
• To elucidate the mechanism underlying PSG-CRIPT interactions, moving beyond simple two-state models.
• To understand how supertertiary structure conformational changes influence protein-protein interactions.

Main Methods:

• Analysis of binding kinetics using the PSG supramodule and CRIPT.
• Characterization of conformational states and their interconversion rates.
• Assessment of ligand binding affinities and rates for different conformational states.

Main Results:

• PSG binds CRIPT through a complex mechanism involving two interconverting conformational states on the second timescale.
• Both conformational states exhibit similar binding affinities for a CRIPT peptide but differ in binding rates.
• CRIPT binding induces a slight shift in the distribution of PSG's conformational states.

Conclusions:

• Protein-protein interactions mediated by multidomain proteins like PSD-95 are more complex than simple two-state models.
• Conformational transitions within supertertiary structures play a significant role in modulating ligand binding.
• These findings provide insights into how structural dynamics shape the energy landscape of protein interactions in cellular signaling.