title: Regulation of PRDX1 peroxidase activity by Pin1.
abstract: 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 (Shc) . 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 ( 90) -Pro ( 91) motif of PRDX1, and this interaction is abolished when the Thr ( 90) 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 ( 90) 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.
authors: Expression Engineering Group, Bioprocessing Technology Institute, A*STAR (Agency for Science, Technology and Research), Singapore.
authors: Kai Ling
authors: KL
authors: Chu
authors: Qiao Jing
authors: QJ
authors: Lew
authors: Vikneswari
authors: V
authors: Rajasegaran
authors: Jing Ting
authors: JT
authors: Kung
authors: Lu
authors: L
authors: Zheng
authors: Qiaoyun
authors: Q
authors: Yang
authors: Rachel
authors: R
authors: Shaw
authors: Nge
authors: N
authors: Cheong
authors: Yih-Cherng
authors: YC
authors: Liou
authors: Sheng-Hao
authors: SH
authors: Chao
mesh_terms: D000375:Aging; D000818:Animals; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D051379:Mice; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D010084:Oxidation-Reduction; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D054464:Peroxiredoxins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D054648:Protein Phosphatase 2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D006861:Hydrogen Peroxide; C515940:PRDX1 protein, human; D054464:Peroxiredoxins; D054648:Protein Phosphatase 2; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse
keywords: PP2A; PRDX1; Pin1; aging and reactive oxygen species; p66Shc; phosphorylation