Calmodulin-dependent regulation of mammalian nitric oxide synthase

Research output: Contribution to journalArticlepeer-review

Abstract

The nitric oxide synthases are large, modular, dimeric enzymes composed of a reductase domain, which is related to cytochrome P450 reductase, and a structurally unique oxygenase domain containing a Cys-ligated haem. Both the neuronal and endothelial isoforms are activated by the reversible binding of calmodulin (CaM) at elevated intracellular Ca2+ levels to produce NO as part of a number of cell signalling pathways. Call binds to the linker region between the two domains and activates the enzyme by inducing intramolecular electron transfer. Protein-engineering experiments have shown that a series of unusual autoinhibitory inserts found only in the CaM-dependent NOS isoforms control both CaM binding and the structural rearrangement it induces. These lie in the reductase domain of the enzyme and include a 40-amino-acid autoinhibitory loop in the FMN-binding module, a 30-amino-acid extension to the C-terminus and the CaM-binding site itself. The substrate (NADPH) also plays an important role in defining the CaM-dependence of the reductase domain by inducing a tight conformational lock in the absence of CaM. Both the substrate and the conformational lock appear to be released on CaM binding; the resultant domain mobility leads to activation.

Original languageEnglish
Pages (from-to)502-505
Number of pages4
JournalBiochemical Society Transactions
Volume31
Publication statusPublished - Jun 2003

Keywords

  • autoinhibition
  • calmodulin
  • cytochrome C
  • electron transfer
  • nitric oxide
  • reductase domain
  • ELECTRON-TRANSFER
  • REDUCTASE DOMAIN
  • FLAVIN
  • MODULATION
  • ISOFORMS
  • FMN

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