4RKY: Crystal Structure Of Dj-1 Isoform X1

Emerging evidence suggests that oxidative/nitrosative stress, as occurs during aging, contributes to the pathogenesis of Parkinson's disease (PD). In contrast, detoxification of reactive oxygen species and reactive nitrogen species can protect neurons. DJ-1 has been identified as one of several recessively inherited genes whose mutation can cause familial PD, and inactivation of DJ-1 renders neurons more susceptible to oxidative stress and cell death. DJ-1 is also known to regulate the activity of the phosphatase and tensin homolog (PTEN), which plays a critical role in neuronal cell death in response to various insults. However, mechanistic details delineating how DJ-1 regulates PTEN activity remain unknown. Here, we report that PTEN phosphatase activity is inhibited via a transnitrosylation reaction [i.e., transfer of a nitric oxide (NO) group from the cysteine residue of one protein to another]. Specifically, we show that DJ-1 is S-nitrosylated (forming SNO-DJ-1); subsequently, the NO group is transferred from DJ-1 to PTEN by transnitrosylation. Moreover, we detect SNO-PTEN in human brains with sporadic PD. Using x-ray crystallography and site-directed mutagenesis, we find that Cys106 is the site of S-nitrosylation on DJ-1 and that mutation of this site inhibits transnitrosylation to PTEN. Importantly, S-nitrosylation of PTEN decreases its phosphatase activity, thus promoting cell survival. These findings provide mechanistic insight into the neuroprotective role of SNO-DJ-1 by elucidating how DJ-1 detoxifies NO via transnitrosylation to PTEN. Dysfunctional DJ-1, which lacks this transnitrosylation activity due to mutation or prior oxidation (e.g., sulfonation) of the critical cysteine thiol, could thus contribute to neurodegenerative disorders like PD.
PDB ID: 4RKYDownload
MMDB ID: 132001
PDB Deposition Date: 2014/10/14
Updated in MMDB: 2015/08
Experimental Method:
x-ray diffraction
Resolution: 1.5  Å
Source Organism:
Similar Structures:
Biological Unit for 4RKY: dimeric; determined by author and by software (PISA)
Molecular Components in 4RKY
Label Count Molecule
Proteins (2 molecules)
Protein Dj-1(Gene symbol: PARK7)
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB