title: Thioredoxin catalyzes the S-nitrosation of the caspase-3 active site cysteine.
abstract: Nitric oxide (NO) signaling through the formation of cGMP is well established; however, there seems to be an increasing role for cGMP-independent NO signaling. Although key molecular details remain unanswered, S-nitrosation represents an example of cGMP-independent NO signaling. This modification has garnered recent attention as it has been shown to modulate the function of several important biochemical pathways. Although an analogy to O-phosphorylation can be drawn, little is known about protein nitrosothiol regulation in vivo. In solution, NO readily reacts with oxygen to yield a nitrosating agent, but this process alone provides no specificity for nitrosation. This lack of specificity is exemplified by the in vitro poly-S-nitrosation of caspase-3 (Casp-3, ref. 6) and the ryanodine receptor. Previous in vivo work with Casp-3 suggests that a protein-assisted process may be responsible for selective S-nitrosation of the catalytic cysteine (Cys163). We demonstrated that a single cysteine in thioredoxin (Trx) is capable of a targeted, reversible transnitrosation reaction with Cys163 of Casp-3. A greater understanding of how S-nitrosation is mediated has broad implications for cGMP-independent signaling. The example described here also suggests a new role for Trx in the regulation of apoptosis.
authors.affiliation: Department of Chemistry, 211 Lewis Hall, University of California Berkeley, Berkeley, California 94720-1460, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Mitchell
authors.forename: Michael A
authors.initials: MA
authors.lastname: Marletta
mesh_terms: D017209:Apoptosis; D001665:Binding Sites / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000737:chemistry*; D002384:Catalysis; D003545:Cysteine / Q000737:chemistry*; D007700:Kinetics; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism*; D015538:Nitrosation; D015398:Signal Transduction; D013879:Thioredoxins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D009569:Nitric Oxide; D013879:Thioredoxins; D053148:Caspase 3; D020169:Caspases; D003545:Cysteine