N‐terminal domain swapping and metal ion binding in nitric oxide synthase dimerization
Open accessAbstract
Nitric oxide synthase oxygenase domains (NOS(ox)) must bind tetrahydrobiopterin and dimerize to be active. New crystallographic structures of inducible NOS(ox) reveal that conformational changes in a switch region (residues 103-111) preceding a pterin-binding segment exchange N-terminal beta-hairpin hooks between subunits of the dimer. N-terminal hooks interact primarily with their own subunits in the 'unswapped' structure, and two switch region cysteines (104 and 109) from each subunit ligate a single zinc ion at the dimer interface. N-terminal hooks rearrange from intra- to intersubunit interactions in the 'swapped structure', and Cys109 forms a self-symmetric disulfide bond across the dimer interface. Subunit association and activity are adversely affected by mutations in the N-terminal hook that disrupt interactions across the dimer interface only in the swapped structure. Residue conservation and electrostatic potential at the NOS(ox) molecular surface suggest likely interfaces outside the switch region for electron transfer from the NOS reductase domain. The correlation between three-dimensional domain swapping of the N-terminal hook and metal ion release with disulfide formation may impact inducible nitric oxide synthase (i)NOS stability and regulation in vivo.
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The dimeric structure of NOS is held together by interactions between the oxygenase domains, including formation of a Zn/4S cluster with two cysteines from each NOS monomer.
“The dimeric structure of NOS is held together by interactions between the oxygenase domains, and among these interactions, the formation of a Zn/4S cluster with the participation of two cysteines from each NOS monomer (195).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [195]
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Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
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Self-citation
- Authors
- Crane, B. R., Rosenfeld, R. J., Arvai, A. S., Ghosh, D. K., Ghosh, S., Tainer, J. A., Stuehr, D. J., & Getzoff, E. D.
- Affiliations
- California Institute of Technology (US)
- Scripps Research Institute (US)
- Cleveland Clinic (US)
- Corresponding author
- Crane, Brian R.
- Getzoff, Elizabeth D.
- Venue
- The EMBO Journal
- Published
- 1999-11-15
- Volume
- 18
- Issue
- 22
- Pages
- 6271-6281
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1171690
- OpenAlex
- W2160004875
- Cited by
- 110
- References
- 70
- Citations by year
- 2025: 2 · 2021: 2 · 2020: 4 · 2019: 2 · 2018: 1 · 2017: 2 · 2016: 3 · 2015: 4 · 2014: 3 · 2013: 3 · 2012: 6
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL058883, HL58883)
- National Cancer Institute (CA-53914)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- inducible nitric oxide synthase, zinc binding, disulfide bond formation, subunit dimerization, switch regions, protein stability, enzyme regulation
- MeSH terms
- Amino Acid Sequence, Animals, Binding Sites, Cysteine, Hydrogen Bonding, Models, Molecular, Molecular Sequence Data, Recombinant Proteins, Software, Zinc, Conserved Sequence, Protein Structure, Secondary, Crystallography, X-Ray, Nitric Oxide Synthase, Dimerization, Protein Structure, Quaternary, Macromolecular Substances, Mice, Nitric Oxide Synthase Type II, Static Electricity
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