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J. Biol. Chem., Vol. 277, Issue 34, 31020-31030, August 23, 2002
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From the Homodimer formation activates all
nitric-oxide synthases (NOSs). It involves the interaction between two
oxygenase domains (NOSoxy) that each bind heme and
(6R)-tetrahydrobiopterin (H4B) and catalyze NO synthesis
from L-Arg. Here we compared three NOSoxy isozymes
regarding dimer strength, interface composition, and the ability of
L-Arg and H4B to stabilize the dimer, promote its formation, and protect it from proteolysis. Urea dissociation studies
indicated that the relative dimer strengths were NOSIIIoxy
Distinct Dimer Interaction and Regulation in
Nitric-oxide Synthase Types I, II, and III*
,,,¶
Department of Immunology, Lerner Research
Institute, The Cleveland Clinic, Cleveland, Ohio 44195 and the
§ Department of Molecular Biology, Skaggs Institute for
Chemical Biology, The Scripps Research Institute,
La Jolla, California 92037
NOSIoxy > NOSIIoxy (endothelial NOSoxy (eNOSoxy) neuronal NOSOXY (nNOSoxy) > inducible NOSoxy (iNOSoxy)). Dimer strengths of the full-length NOSs had the same rank order as judged by their urea-induced loss of NO synthesis activity. NOSoxy dimers containing L-Arg plus H4B exhibited the greatest resistance to
urea-induced dissociation followed by those containing either molecule
and then by those containing neither. Analysis of crystallographic structures of eNOSoxy and iNOSoxy dimers showed more intersubunit contacts and buried surface area in the dimer interface of eNOSoxy than
iNOSoxy, thus revealing a potential basis for their different stabilities. L-Arg plus H4B promoted dimerization of
urea-generated iNOSoxy and nNOSoxy monomers, which otherwise was
minimal in their absence, and also protected both dimers against
trypsin proteolysis. In these respects, L-Arg alone was
more effective than H4B alone for nNOSoxy, whereas for iNOSoxy the
converse was true. The eNOSoxy dimer was insensitive to proteolysis
under all conditions. Our results indicate that the three NOS isozymes,
despite their general structural similarity, differ markedly in their
strengths, interfaces, and in how L-Arg and H4B influence
their formation and stability. These distinguishing features may
provide a basis for selective control and likely help to regulate each
NOS in its particular biologic milieu.
*
This work was supported by National Institutes of Health
Grants CA53914 (to D. J. S.) and HL58883-05 (to E. D. G.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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