Internal recognition through PDZ domain plasticity in the Par-6-Pals1 complex

Area of Science:

• Molecular Biology
• Cell Biology
• Structural Biology

Background:

• PDZ domains are crucial protein interaction modules.
• Typically, PDZ domains bind C-terminal ligands.
• Non-C-terminal, or internal, ligand binding by PDZ domains is less common but known.

Purpose of the Study:

• To investigate the structural basis of internal ligand binding by the Par-6 PDZ domain.
• To understand how binding of the internal ligand Pals1 affects Par-6 interactions.
• To elucidate the role of these interactions in cell polarity regulation.

Main Methods:

• X-ray crystallography to determine the structure of the Pals1-Par-6 PDZ complex.
• Biochemical assays to study protein-ligand interactions.
• Analysis of conformational changes upon ligand binding.

Main Results:

• The Par-6 PDZ domain undergoes structural deformation to accommodate the internal Pals1 ligand.
• Binding of Pals1 to the Par-6 PDZ domain is independent of Cdc42.
• Cdc42 binding to an adjacent CRIB domain regulates C-terminal ligand binding.

Conclusions:

• PDZ domains can bypass the typical C-terminal requirement for ligand binding through structural adaptation.
• Complex cooperative and competitive interactions involving Par-6, Pals1, and Cdc42 are critical for cell polarity.
• Structural plasticity of PDZ domains allows for diverse binding modes and regulatory mechanisms.