4RKY

Crystal structure of DJ-1 isoform X1

Summary for 4RKY

• Entry DOI: 10.2210/pdb4rky/pdb
• Related: 4RKW
• Descriptor: Protein DJ-1 (2 entities in total)
• Functional Keywords: nitrosylation, brain, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 19946.05

Authors

Liddington, R.C. (deposition date: 2014-10-14, release date: 2015-08-26, Last modification date: 2024-11-27)

Primary citation

Choi, M.S.,Nakamura, T.,Cho, S.J.,Han, X.,Holland, E.A.,Qu, J.,Petsko, G.A.,Yates, J.R.,Liddington, R.C.,Lipton, S.A.
Transnitrosylation from DJ-1 to PTEN attenuates neuronal cell death in parkinson's disease models.
J.Neurosci., 34:15123-15131, 2014

PubMed Abstract: 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.

PubMed: 25378175
DOI: 10.1523/JNEUROSCI.4751-13.2014

Experimental method

X-RAY DIFFRACTION (1.5 Å)