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Papers In Press, published online ahead of print July 7, 2003
Immunology Dept., Cleveland Clinic, Cleveland, OH 44195
Corresponding Author: stuehrd{at}ccf.org
Nitric oxide (NO) is a signal molecule produced in animals by three different NO synthases. Of these, only NOS I (nNOS) is expressed as catalytically active N-terminally truncated forms that are missing either an N-terminal leader sequence required for protein-protein interactions, or are missing the leader sequence plus three core structural motifs that in other NOS are required for dimer assembly and catalysis. To understand how the N-terminal elements impact nNOS structure-function, we generated, purified, and extensively characterized variants that were missing the N-terminal leader sequence (D296nNOS) or missing the leader sequence plus the three core motifs (D349nNOS). Eliminating the leader sequence had no impact on nNOS structure or catalysis. In contrast, additional removal of the core elements weakened but did not destroy the dimer interaction, slowed ferric heme reduction and reactivity of a heme-dioxy intermediate, and caused a ten-fold poorer affinity toward substrate L-arginine. This created a nNOS variant with slower and less coupled NO synthesis that is predisposed to generate reactive oxygen species along with NO. Our findings help justify the existence of nNOS N-terminal splice variants and identify specific catalytic changes that create functional differences among them.
J. Biol. Chem, 10.1074/jbc.M304456200
Submitted on April 29, 2003
Revised on June 25, 2003
Accepted on July 7, 2003
Distinct influence of N-terminal elements on neuronal nitric oxide synthase structure and catalysis
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