Cysteine regulation of protein function – as exemplified by NMDA-receptor modulation
Abstract
Until recently cysteine residues, especially those located extracellularly, were thought to be important for metal coordination, catalysis and protein structure by forming disulfide bonds - but they were not thought to regulate protein function. However, this is not the case. Crucial cysteine residues can be involved in modulation of protein activity and signaling events via other reactions of their thiol (sulfhydryl; -SH) groups. These reactions can take several forms, such as redox events (chemical reduction or oxidation), chelation of transition metals (chiefly Zn(2+), Mn(2+) and Cu(2+)) or S-nitrosylation [the catalyzed transfer of a nitric oxide (NO) group to a thiol group]. In several cases, these disparate reactions can compete with one another for the same thiol group on a single cysteine residue, forming a molecular switch composed of a latticework of possible redox, NO or Zn(2+) modifications to control protein function. Thiol-mediated regulation of protein function can also involve reactions of cysteine residues that affect ligand binding allosterically. This article reviews the basis for these molecular cysteine switches, drawing on the NMDA receptor as an exemplary protein, and proposes a molecular model for the action of S-nitrosylation based on recently derived crystal structures.
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Redox regulation is particularly strong for GRIN2A-containing NMDARs, where a region of the N-terminus is sufficient to mediate the potentiation of currents by reducing agents such as dithiothreitol or GSH.
“Redox regulation is particularly strong for GRIN2A-containing NMDARs, where a region of the N-terminus is sufficient to mediate the potentiation of currents by reducing agents such as Dithiothreitol or GSH 68,69 .”
From Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis (2016) · cites this paper as [69]
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- Authors
- Lipton, S. A., Choi, Y.-B., Takahashi, H., Zhang, D., Li, W., Godzik, A., & Bankston, L. A.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Lipton, Stuart A.
- Venue
- Trends in Neurosciences
- Publisher
- Elsevier BV
- Published
- 2002-09
- Volume
- 25
- Issue
- 9
- Pages
- 474-480
- ISSN
- 0166-2236 (ISSN-L)
- OpenAlex
- W2051369940
- Cited by
- 375
- References
- 42
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 14 · 2023: 14 · 2022: 12 · 2021: 19 · 2020: 18 · 2019: 23 · 2018: 15 · 2017: 17 · 2016: 11 · 2015: 13 · 2014: 22 · 2013: 9 · 2012: 25
- FWCI
- 0.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Trends in Neurosciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Eye Institute (R01 EY09024, R01 EY 05477, R01EY009024, R01EY005477)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD29587, P01HD029587)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Keywords
- cysteine residues, sulfhydryl groups, NMDA receptor, S-nitrosylation, redox regulation, metal chelation, zinc, manganese, copper, molecular switches, protein function regulation, nitric oxide signaling
- MeSH terms
- Animals, Cysteine, Humans, Models, Molecular, Nitric Oxide, Oxidation-Reduction, Sulfhydryl Compounds, Receptors, N-Methyl-D-Aspartate, Protein Structure, Tertiary, S-Nitrosothiols
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