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J Biol Chem, Vol. 273, Issue 10, 5451-5454, March 6, 1998
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From the Calmodulin (CaM) binding activates neuronal
nitric-oxide synthase (nNOS) catalytic functions and also up-regulates
electron transfer into its flavin and heme centers. Here, we utilized
seven tight binding CaM-troponin C chimeras, which variably activate nNOS NO synthesis to examine the relationship between CaM domain structure, activation of catalytic functions, and control of internal electron transfer at two points within nNOS. Chimeras that were singly
substituted with troponin C domains 4, 3, 2, or 1 were increasingly
unable to activate NO synthesis, but all caused some activation of
cytochrome c reduction compared with CaM-free nNOS. The
magnitude by which each chimera activated NO synthesis was approximately proportional to the rate of heme iron reduction supported
by each chimera, which varied from 0% to ~80% compared with native
CaM and remained coupled to NO synthesis in all cases. In contrast,
chimera activation of cytochrome c reduction was not always
associated with accelerated reduction of nNOS flavins, and certain
chimeras activated cytochrome c reduction without triggering heme iron reduction. We conclude: 1) CaM effects on electron
transfer at two points within nNOS can be functionally separated. 2)
CaM controls NO synthesis by governing heme iron reduction, but
enhances reductase activity by two mechanisms, only one of which is
associated with an increased rate of flavin reduction.
Department of Immunology, The Cleveland
Clinic Research Institute, Cleveland, Ohio 44195, the
¶ Departments of Medicine and Pharmacology, Duke University
Medical Center, Durham, North Carolina 27710, and the Institut
fur Pharmakologie und Toxikologie, Karl-Franzens-Universitat Graz,
Universitatsplatz 2, A-8010 Graz, Austria
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