A Specific pSer/Thr-Pro Motif Generates Interdomain Communication Bifurcations of Two Modes of Pin1 in Solution Nuclear Magnetic Resonance.

Abstract

Peptides mediate the interdomain communication of Pin1 (peptidyl-prolyl cis-trans isomerase) and can regulate its conformation and biochemical functions, providing an idea for drug design using Pin1. Two template peptide sequences have been widely used in the extended or compact state of Pin1 (Cdc25C, E-Q-P-L-pT-P-V-T-D-L; Pintide, W-F-Y-pS-P-R). The way in which specific pSer/Thr-Pro peptides regulate interdomain communication to achieve the opposite state is not clear. In this study, we subdivided the sequence composition of eight types of modified peptides and investigated the interaction with Pin1 by solution nuclear magnetic resonance and molecular dynamics. Demonstrating sequence dependence on the pSer-Pro or pThr-Pro motif and different residues in anchoring the WW domain, the Pin peptide (Pintide, PintideT, Pin25C, and Pin25CT) transmits this concentration accumulation to the PPIase domain, thus exhibiting two anchoring tendencies. However, the Cdc peptide (Cdc25C, Cdc25CS, Cdctide, and CdctideS) has a low binding energy that makes it difficult for the conformation to reach a steady state. In addition, Pin1 is influenced by both compact and extended states, regulated precisely by the sequence as well as by threonine or serine. These results provide new insight into the interdomain communication of Pin1 via pSer/Thr-Pro peptide binding.