Emerging role of protein-protein transnitrosylation in cell signaling pathways.
CONCLUSIONS
Protein S-nitrosylation, a covalent reaction of a nitric oxide (NO) group with a critical protein thiol (or more properly thiolate anion), mediates an important form of redox-related signaling as well as aberrant signaling in disease states.


BACKGROUND
A growing literature suggests that over 3000 proteins are S-nitrosylated in cell systems. Our laboratory and several others have demonstrated that protein S-nitrosylation can regulate protein function by directly inhibiting catalytically active cysteines, by reacting with allosteric sites, or via influencing protein-protein interaction. For example, S-nitrosylation of critical cysteine thiols in protein-disulfide isomerase and in parkin alters their activity, thus contributing to protein misfolding in Parkinson's disease.


RESULTS
However, the mechanism by which specific protein S-nitrosylation occurs in cell signaling pathways is less well investigated. Interestingly, the recent discovery of protein-protein transnitrosylation reactions (transfer of an NO group from one protein to another) has revealed a unique mechanism whereby NO can S-nitrosylate a particular set of protein thiols, and represents a major class of nitrosylating/denitrosylating enzymes in mammalian systems. In this review, we will discuss recent evidence for transnitrosylation reactions between (i) hemoglobin/anion exchanger 1, (ii) thioredoxin/caspase-3, (iii) X-linked inhibitor of apoptosis/caspase-3, (iv) GAPDH-HDAC2/SIRT1/DNA-PK, and (v) Cdk5/dynamin related protein 1 (Drp1). This review also discusses experimental techniques useful in characterizing protein-protein transnitrosylations.


CONCLUSIONS
Elucidation of additional transnitrosylation cascades will further our understanding of the enzymes that catalyze nitrosation, thereby contributing to NO-mediated signaling pathways.
Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA. tnakamura@sanfordburnham.org
Tomohiro
T
Nakamura
Stuart A
SA
Lipton
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D016923:Cell Death; D003545:Cysteine / Q000031:analogs & derivatives / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology; D015538:Nitrosation; D010084:Oxidation-Reduction; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000378:metabolism; D026403:S-Nitrosothiols / Q000378:metabolism; D015398:Signal Transduction
D011506:Proteins; D026403:S-Nitrosothiols; D009569:Nitric Oxide; C021315:S-nitrosocysteine; D003545:Cysteine