Hinge-Shift Mechanism Modulates Allosteric Regulations in Human Pin1.

Allostery, which is regulation from distant sites, plays a major role in biology. While traditional allostery is described in terms of conformational change upon ligand binding as an underlying principle, it is possible to have allosteric regulations without significant conformational change through modulating the conformational dynamics by altering the local effective elastic modulus of the protein upon ligand binding. Pin1 utilizes this dynamic allostery to regulate its function. It is a modular protein containing a WW domain and a larger peptidyl prolyl isomerase domain (PPIase) that isomerizes phosphoserine/threonine-proline (pS/TP) motifs. The WW domain serves as a docking module, whereas catalysis solely takes place within the PPIase domain. Here, we analyze the change in the dynamic flexibility profile of the PPIase domain upon ligand binding to the WW domain. Substrate binding to the WW domain induces the formation of a new rigid hinge site around the interface of the two domains and loosens the flexibility of a rigid site existing in the Apo form around the catalytic site. This hinge-shift mechanism enhances the dynamic coupling of the catalytic positions with the PPIase domain, where the rest of the domain can cooperatively respond to the local conformational changes around the catalytic site, leading to an increase in catalytic efficiency.