Conformational dynamics and multi-modal interaction of Paxillin with the Focal Adhesion Targeting Domain

Area of Science:

• Cell Biology
• Structural Biology
• Biochemistry

Background:

• Paxillin (PXN) and focal adhesion kinase (FAK) are critical for the focal adhesion complex, linking the cytoskeleton to the extracellular matrix.
• PXN's intrinsically disordered N-terminal domain binds FAK's C-terminal targeting domain (FAT), localizing FAK to focal adhesions.
• PXN acts as a scaffold, recruiting proteins that regulate cell migration and survival.

Purpose of the Study:

• To elucidate the structural dynamics of the PXN-FAT complex.
• To understand how PXN's conformational changes upon FAT binding influence cellular functions.

Main Methods:

• The study utilized biophysical techniques to analyze the conformational states of the PXN disordered region upon binding to FAT.
• Analysis focused on identifying conserved contacts and their role in complex stability.

Main Results:

• The PXN disordered region undergoes significant conformational restriction when binding to FAT, forming a flexible 48-kDa complex with four interconverting states.
• Each conformational state exhibits unique, conserved contacts involving disordered and glutamine-rich regions.
• Conserved intramolecular contacts contribute to the stability of the FAT-bound complex through high entropy.

Conclusions:

• The PXN-FAT interaction results in a multi-state conformational ensemble, providing a structural basis for dynamic cellular processes.
• Understanding these conformational shifts is crucial for comprehending how cellular networks are rewired by external stimuli like ligand binding and phosphorylation, potentially leading to phenotypic switching.