Gears-In-Motion: The Interplay of WW and PPIase Domains in Pin1.

Yew Mun Lee,Yih-Cherng Liou

doi:10.3389/fonc.2018.00469

Abstract

Pin1 belongs to the family of the peptidyl-prolyl cis-trans isomerase (PPIase), which is a class of enzymes that catalyze the cis/trans isomerization of the Proline residue. Pin1 is unique and only catalyzes the phosphorylated Serine/Threonine-Proline (S/T-P) motifs of a subset of proteins. Since the discovery of Pin1 as a key protein in cell cycle regulation, it has been implicated in numerous diseases, ranging from cancer to neurodegenerative diseases. The main features of Pin1 lies in its two main domains: the WW (two conserved tryptophan) domain and the PPIase domain. Despite extensive studies trying to understand the mechanisms of Pin1 functions, how these two domains contribute to the biological roles of Pin1 in cellular signaling requires more investigations. The WW domain of Pin1 is known to have a higher affinity to its substrate than that of the PPIase domain. Yet, the WW domain seems to prefer the trans configuration of phosphorylated S/T-P motif, while the PPIase catalyzes the cis to trans isomerasion. Such contradicting information has generated much confusion as to the actual mechanism of Pin1 function. In addition, dynamic allostery has been suggested to be important for Pin1 function. Henceforth, in this review, we will be looking at the progress made in understanding the function of Pin1, and how these understandings can aid us in overcoming the diseases implicated by Pin1 such as cancer during drug development.

Highlights

Posttranslational modifications (PTMs) introduce diversity to the functions of many proteins in the cellular proteome
Interactors which are known kinases themselves as reflected in the IntAct Molecular Interaction database [67]. In another model termed the catalysis-first binding model (Figure 3C), it is believed that the phosphorylation of S/T-P motif on the target substrate for WW domain binding requires the peptidyl-prolyl cis-trans isomerase (PPIase) function of Pin1 [57]
The authors suggest that Pin1 could interact with its biological substrate via the simultaneous binding model (Figure 3D). They noticed that phosphorylated consensus site ser/thr-pro (pS/T-P) motifs that have an addition P residue in the +1 position, pS/T-P-P, seem to be targeted by the WW domain but not the PPIase domain of Pin1

Summary

INTRODUCTION

Posttranslational modifications (PTMs) introduce diversity to the functions of many proteins in the cellular proteome. In another model termed the catalysis-first binding model (Figure 3C), it is believed that the phosphorylation of S/T-P motif on the target substrate for WW domain binding requires the PPIase function of Pin1 [57] This proposition was put forth by the observation that in all the known structures of the WW domain bound substrate peptides, the identified binding site is present in a trans configuration state [56, 57, 68]. The authors suggest that Pin could interact with its biological substrate via the simultaneous binding model (Figure 3D) In their study, they noticed that pS/T-P motifs that have an addition P residue in the +1 position, pS/T-P-P, seem to be targeted by the WW domain but not the PPIase domain of Pin. This brings a question whether cellular permeability could be major limitation in their development

Mode of discovery

Some variant inactive in cell lines

Phenotypic association