Pin1 cysteine-113 oxidation inhibits its catalytic activity and cellular function in Alzheimer's disease

Abstract

The unique proline isomerase Pin1 is pivotal for protecting against age-dependent neurodegeneration in Alzheimer’s disease (AD), with its inhibition providing a molecular link between tangle and plaque pathologies. Pin1 is oxidatively modified in human AD brains, but little is known about its regulatory mechanisms and pathological significance of such Pin1 modification. In this paper, our determination of crystal structures of oxidized Pin1 reveals a series of Pin1 oxidative modifications on Cys113 in a sequential fashion. Cys113 oxidization is further confirmed by generating antibodies specifically recognizing oxidized Cys113 of Pin1. Furthermore, Pin1 oxidation on Cys113 inactivates its catalytic activity in vitro, and Ala point substitution of Cys113 inactivates the ability of Pin1 to isomerize tau as well as to promote protein turnover of tau and APP. Moreover, redox regulation affects Pin1 subcellular localization and Pin1-mediated neuronal survival in response to hypoxia treatment. Importantly, Cys113-oxidized Pin1 is significantly increased in human AD brain comparing to age-matched controls. These results not only identify a novel Pin1 oxidation site to be the critical catalytic residue Cys113, but also provide a novel oxidative regulation mechanism for inhibiting Pin1 activity in AD. These results suggest that preventing Pin1 oxidization might help to reduce the risk of AD.

Oxidative stress in Alzheimer disease and mild cognitive impairment: evidence from human data provided by redox proteomics

“…Pin1 is also intricately involved in many stages of the cell cycle through direct contact with target proteins as well as indirect action through the regulation of important kinases and phosphatases (Keeney et al 2012;Driver and Lu 2010;Lin et al 2015). We recently reported that the active site Cys-113 residue is oxidatively modified to sulfonic acid in AD brain, and we posit that this modification may account for the decreased Pin1 activity we have observed in AD brain (Chen et al 2015;Sultana et al 2006a, b, c).…”

Pin1 mediates Aβ 42 -induced dendritic spine loss

“…These data suggested that Pin1 was somehow inactivated in AD lysates. Pin1 can be oxidized at Cys 113 , blocking activity (9) or inhibited by outside-in glutamatergic signaling (10). To identify the mechanism, we utilized mouse synaptoneurosomes, a highly enriched preparation of pre- and post-synaptic neuronal connections from brain.…”

“…The isomerase activity of Pin1 is lost due to oxidation of Cys 113 , a critical amino acid within its active site (9). Whether alterations in inside-out signaling, especially at synaptic sites, can affect Pin1 activity or steady-state protein amounts during AD evolution is unknown.…”

A simple isotopic labeling method to study cysteine oxidation in Alzheimer’s disease: oxidized cysteine-selective dimethylation (OxcysDML)

“…These modifications are likely due to elevated oxidative stress and are involved in various cellular pathways, such as glycolysis, calcium homeostasis, and vesicle transport [12,14,15]. More recently, Cys113 oxidation of proline isomerase, Pin1, in postmortem AD brain has been associated with catalytic inactivity of Pin1 [16].…”