Pin1 isomerizes the phosphorylated Ser/Thr-Pro peptide bonds and regulates the functions of its binding proteins by inducing conformational changes. Involvement of Pin1 in the aging process has been suggested based on the phenotype of Pin1-knockout mice and its interaction with lifespan regulator protein, p66^{. In this study, we utilize a proteomic approach and identify peroxiredoxin 1 (PRDX1), another regulator of aging, as a novel Pin1 binding protein. Pin1 binds to PRDX1 through interacting with the phospho-Thr}^-Pro^{motif of PRDX1, and this interaction is abolished when the Thr}^{of PRDX1 is mutated. The Pin1 binding motif, Thr-Pro, is conserved in the 2-Cys PRDXs, PRDX1–4 and the interactions between Pin1 and PRDX2–4 are also demonstrated. An increase in hydrogen peroxide buildup and a decrease in the peroxidase activity of 2-Cys PRDXs were observed in}Pin1^−/− mouse embryonic fibroblasts (MEFs), with the activity of PRDXs restored when Pin1 was re-introduced into the cells. Phosphorylation of PRDX1 at Thr^{has been shown to inhibit its peroxidase activity; however, how exactly the activity of PRDX1 is regulated by phosphorylation still remains unknown. Here, we demonstrate that Pin1 facilitates the protein phosphatase 2A-mediated dephosphorylation of PRDX1, which helps to explain the accumulation of the inactive phosphorylated form of PRDX1 in}Pin1^−/− MEFs. Collectively, we identify Pin1 as a novel PRDX1 binding protein and propose a mechanism for Pin1 in regulating the metabolism of reactive oxygen species in cells.

Keywords: Pin1, PRDX1, p66^{, PP2A, phosphorylation, aging and reactive oxygen species}

Abstract

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Acknowledgments

We would like to thank Dr. Kun Ping Lu for providing the Pin1^+/+ and Pin1^−/− MEFs and Dr. Peiqing Zhang for critical review of the manuscript. This work is supported by the Agency for Science, Technology and Research (A*STAR), Singapore.

Acknowledgments

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Disclosure of Potential Conflicts of Interest

Footnotes

Previously published online: www.landesbioscience.com/journals/cc/article/23916

Footnotes

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