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

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          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.

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          Most cited references103

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          On the nature of allosteric transitions: A plausible model

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            A human peptidyl-prolyl isomerase essential for regulation of mitosis.

            The NIMA kinase is essential for progression through mitosis in Aspergillus nidulans, and there is evidence for a similar pathway in other eukaryotic cells. Here we describe the human protein Pin1, a peptidyl-prolyl cis/trans isomerase (PPIase) that interacts with NIMA. PPIases are important in protein folding, assembly and/or transport, but none has so far been shown to be required for cell viability. Pin1 is nuclear PPIase containing a WW protein interaction domain, and is structurally and functionally related to Ess1/Ptf1, an essential protein in budding yeast. PPIase activity is necessary for Ess1/Pin1 function in yeast. Depletion of Pin1/Ess1 from yeast or HeLa cells induces mitotic arrest, whereas HeLa cells overexpressing Pin1 arrest in the G2 phase of the cell cycle. Pin1 is thus an essential PPIase that regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity.
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              Protein kinase C beta and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66Shc.

              The 66-kilodalton isoform of the growth factor adapter Shc (p66Shc) translates oxidative damage into cell death by acting as reactive oxygen species (ROS) producer within mitochondria. However, the signaling link between cellular stress and mitochondrial proapoptotic activity of p66Shc was not known. We demonstrate that protein kinase C beta, activated by oxidative conditions in the cell, induces phosphorylation of p66Shc and triggers mitochondrial accumulation of the protein after it is recognized by the prolyl isomerase Pin1. Once imported, p66Shc causes alterations of mitochondrial Ca2+ responses and three-dimensional structure, thus inducing apoptosis. These data identify a signaling route that activates an apoptotic inducer shortening the life span and could be a potential target of pharmacological approaches to inhibit aging.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                25 October 2018
                2018
                : 8
                : 469
                Affiliations
                Department of Biological Sciences, Faculty of Science, National University of Singapore , Singapore, Singapore
                Author notes

                Edited by: Nan-Shan Chang, National Cheng Kung University, Taiwan

                Reviewed by: Akihide Ryo, Yokohama City University, Japan; Flavio Rizzolio, Università Ca' Foscari, Italy; Brion William Murray, Pfizer (United States), United States

                *Correspondence: Yih-Cherng Liou dbslyc@ 123456nus.edu.sg

                This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2018.00469
                6232885
                30460195
                369243bd-8681-4621-b683-13495eb5e17b
                Copyright © 2018 Lee and Liou.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 24 August 2018
                : 04 October 2018
                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 116, Pages: 11, Words: 9778
                Categories
                Oncology
                Review

                Oncology & Radiotherapy
                pin1,ww domain,peptidyl-prolyl cis/trans isomerase (ppiase),phosphorylation,interdomain communication,cancer target,drug development

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