Hinge-Shift Mechanism Modulates Allosteric Regulations in Human Pin1.

Area of Science:

• Biochemistry
• Molecular Biology
• Enzymology

Background:

• Allostery regulates biological processes through distant binding sites.
• Traditional allostery involves conformational changes; dynamic allostery modulates protein dynamics.
• Pin1 protein, with WW and peptidyl prolyl isomerase (PPIase) domains, catalyzes phosphoserine/threonine-proline motif isomerization.

Purpose of the Study:

• To investigate how ligand binding to Pin1's WW domain affects the PPIase domain's dynamic flexibility.
• To elucidate the mechanism of dynamic allostery in Pin1 function.

Main Methods:

• Analysis of dynamic flexibility profiles of the Pin1 PPIase domain.
• Comparison of flexibility in ligand-bound (holo) versus unbound (apo) states.

Main Results:

• Substrate binding to the WW domain creates a new rigid hinge near the domain interface.
• Ligand binding loosens a previously rigid site around the catalytic center in the PPIase domain.
• This hinge-shift mechanism enhances dynamic coupling and cooperativity within the PPIase domain.

Conclusions:

• Pin1 employs dynamic allostery, not just conformational change, for regulation.
• Altering the protein's elastic modulus upon ligand binding enhances catalytic efficiency.
• The hinge-shift mechanism is key to Pin1's allosteric regulation and increased enzyme activity.