Disorder drives cooperative folding in a multidomain protein

Area of Science:

• Protein structure and dynamics
• Microbial pathogenesis
• Biophysics

Background:

• Intrinsically disordered regions (IDRs) are crucial for protein function, mediating interactions and allostery.
• The Staphylococcus aureus surface protein G (SasG) is essential for host colonization and biofilm formation.
• SasG contains intrinsically unfolded E domains that fold upon interaction with neighboring G5 domains.

Purpose of the Study:

• To investigate the role of intrinsically disordered E domains in the cooperative folding of SasG.
• To understand how disorder influences the mechanical stability and structural integrity of SasG.

Main Methods:

• Analysis of protein folding kinetics and cooperativity in SasG.
• Investigating the role of intrinsically unfolded E domains and stable interdomain interfaces.
• Utilizing mutational analysis to disrupt folding nuclei and observe alternative folding pathways.

Main Results:

• Disordered E domains, coupled with stable interdomain interfaces, drive cooperative folding over long distances (10 nm).
• Formation of a folding nucleus initiates rapid, long-range structure formation, crucial for SasG structural integrity.
• Disruption of the normal folding nucleus allows the stable interdomain interface to drive folding via a parallel pathway.

Conclusions:

• Intrinsically disordered regions in SasG are critical for its unique cooperative folding mechanism.
• The interplay between disorder and stable interfaces ensures the maintenance of SasG's structural integrity.
• This mechanism highlights the functional importance of intrinsic disorder in bacterial adhesion proteins.