on August 11, 2016
The dynamic basis for signal propagation in human Pin1-WW.
Understanding how information transfers through large molecular assemblies is an important topic in modern structural biology. These allosteric events are thought to be connected to intrinsic concerted conformational changes happening in the solution. In particular, understanding these conformational fluctuations may shed light on the mechanisms of how some proteins achieve multiple different responses upon binding of different binding partners.
Pin1 is an important regulator of the cell cycle which has a very broad range of interaction partners to which it binds through pS/pT-P motifs. Measurements of binding of Pin1 to ligands with difference in the amino-acids flanking the binding motifs have been shown to introduce different structural changes. However, how these changes happen at the atomistic level have previously been elusive.
In a recent paper appearing in the prestigious journal Structure, Cavalli and co-workers determine an ensemble model of the binding domain of Pin1 (WW). This ensemble reveals the presence of two structural configurations, in which distant sites are changing in a concerted fashion (see Illustration below). Further analyses reveal how these structural differences are tightly connected to the probability to associate to the catalytic domain of Pin1, and how the equilibrium between these states can be modulated by different ligands.
The results reveal a mechanism by which binding partners my recruit Pin1 to perform a specific function. These findings further serves as an atomistic resolution example of the connection between allosteric mechanisms and intrinsic concerted motions in proteins.
The study was financially supported by Danish Council for Independent Research Natural Sciences (DFF-4002-00151).
