Proteomics

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A chemical probe to monitor parkinsonism-associated protein DJ-1 in live cells


ABSTRACT: Oxidative stress is a contingent trigger of Parkinson`s disease (PD). DJ-1, a protein involved in oxidative stress sensing, gained major attention when mutations in its gene were identified in PD patients. Although the study of the corresponding protein function is still in its infancy, a crucial oxidation sensor at a conserved cysteine was linked to the disease. Inspired by inhibition studies with a bacterial homolog of DJ-1 we here screen several amino-epoxycylcohexenones and identify a chemical probe that exhibits specificity for the human protein in various cell lines. The probe selectively labeled the oxidation sensor via nucleophilic attack of the conserved cysteine onto the epoxide ring. This covalent addition occurred only in the reduced state. Whole proteome studies in HeLa, A549 and SHSY5Y cell lines confirmed strong enrichment of solely reduced DJ-1 which was diminished by increasing oxidative stress. The probe thus facilitates the first selective in situ monitoring of DJ-1 in its reduced state and enables studying the function of this important biomarker in dependence of oxidative stress.

INSTRUMENT(S): LTQ Orbitrap XL, Orbitrap Fusion, Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain, Lung, Hela Cell

SUBMITTER: Jonas Drechsel  

LAB HEAD: Stephan A Sieber

PROVIDER: PXD009444 | Pride | 2018-07-17

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
20160527_JD_D4S8_1.raw Raw
20160527_JD_D4S8_2.raw Raw
20160527_JD_D4S8_3.raw Raw
20160527_JD_D8S4_1.raw Raw
20160527_JD_D8S4_2.raw Raw
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Publications

Chemical Probe To Monitor the Parkinsonism-Associated Protein DJ-1 in Live Cells.

Drechsel Jonas J   Mandl Franziska A FA   Sieber Stephan A SA  

ACS chemical biology 20180719 8


Reactive oxygen species (ROS) play an important role in the onset of Parkinson's disease (PD), and deciphering protective mechanisms is a major goal for therapeutic development. Here, DJ-1 (PARK7) gained major attention when a conserved cysteine residue with a putative role in oxidative stress sensing/protection was linked to PD. Inspired by previous studies with a bacterial homologue of DJ-1, several amino-epoxycylcohexenones were screened for enzyme inhibition, and a chemical probe with specif  ...[more]

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