Post-translational Modifications of the Peptidyl-Prolyl Isomerase Pin1

Abstract

The peptidyl-prolyl cis/trans isomerase (PPIase) Pin1 is a unique enzyme that only binds to Ser/Thr-Pro peptide motifs after phosphorylation and regulates the conformational changes of the bond. The Pin1-catalyzed isomerization upon phosphorylation can have profound effects on substrate biological functions, including their activity, stability, assembly, and subcellular localization, affecting its role in intracellular signaling, transcription, and cell cycle progression. The functions of Pin1 are regulated by post-translational modifications (PTMs) in many biological processes, which include phosphorylation, ubiquitination, SUMOylation and oxidation. Phosphorylation of different Pin1 sites regulates Pin1 enzymatic activity, binding ability, localization, and ubiquitination by different kinases under various cellular contexts. Moreover, SUMOylation and oxidation have been shown to downregulate Pin1 activity. Although Pin1 is tightly regulated under physiological conditions, deregulation of Pin1 PTMs contributes to the development of human diseases including cancer and Alzheimer's disease (AD). Therefore, manipulating the PTMs of Pin1 may be a promising therapeutic option for treating various human diseases. In this review, we focus on the molecular mechanisms of Pin1 regulation by PTMs and the major impact of Pin1 PTMs on the progression of cancer and AD.

A Redox-Sensitive Cysteine Is Required for PIN1At Function

“…In previous studies, PIN1At has also been identified as sulfenylated in response to H 2 O 2 treatments ( Liu et al, 2014 ; Wei et al, 2020 ) and persulfidated in standard growing conditions ( Aroca et al, 2017 ). Similarly, the Cys113 of human PIN1 is prone to redox PTMs such as persulfidation and irreversible oxidation (sulfinylation and sulfonylation), in addition to other PTMs such as phosphorylation, acetylation, and SUMOylation ( Chen et al, 2015 ; Innes et al, 2015 ; Longen et al, 2016 ; Chen et al, 2020 ). Of interest, the irreversible oxidation of human PIN1 was associated with various pathologies as mild cognitive impairment or Alzheimer’s disease ( Butterfield et al, 2006 ; Sultana et al, 2006 ) and induces a decrease of reactivity and mislocalization impairing the physiological function of the protein ( Chen et al, 2015 ).…”

Targeting Pin1 for Modulation of Cell Motility and Cancer Therapy

“…In addition to the expression level, post-translational regulation is a crucial way of controlling Pin1 function. To date, post-translational modifications of Pin1 have been identified as phosphorylation, SUMOylation, oxidation, acetylation and ubiquitination [ 3 ]. These modifications change the Pin1 structure at the corresponding sites, leading to alterations in protein stability, cellular localization, protein interactions and enzymatic activity under both physiological and pathological conditions.…”

“…Cells respond to extracellular and intracellular stimuli and elicit various regulatory mechanisms such as epigenetic regulations, allosteric regulations and post-translational modifications (PTMs) to control signal transduction [ 1 , 2 , 3 ]. PTMs are critical and complex regulators, which control many cellular processes by changing protein structure, thereby causing alteration in enzyme activity, protein interaction, protein compartmentalization, protein processing, and protein stability.…”

Cellular Mechanisms of Melatonin: Insight from Neurodegenerative Diseases

“…Recently, melatonin was found to directly bind to DAPK1 and promote DAPK1 protein degradation through the ubiquitin-mediated proteasome pathway, resulting in increased Pin1 activity and eventually decreased tau hyperphosphorylation and tau-related pathologies [ 80 ]. Pin1 is a phosphorylation-specific peptidyl prolyl cis/trans isomerase and has protective effects on tau-related pathology, suggesting that the melatonin–DAPK1–Pin1 axis regulates AD [ 81 , 82 , 83 , 84 ].…”