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Cysteine–Zn²⁺ complexes: unique molecular switches for inducible nitric oxide synthase-derived NO

Research Group Immunobiology, Medical Department of the Heinrich-Heine-University of Düsseldorf, D-40225 Düsseldorf, Germany

¹Correspondence: Research Group Immunobiology 23.12, MED-Heinrich-Heine-University of Düsseldorf, Moorenstr. 5, D-40225 Düsseldorf, Germany. E-mail: kroencke{at}uni-duesseldorf.de

	ABSTRACT

TOP ABSTRACT INTRODUCTION TRANSCRIPTION PROTEIN FOLDING PROTEOLYSIS CONCLUSIONS REFERENCES

 
Nitric oxide (NO) in the low nanomolar range acts as a transcellular messenger molecule to initiate regulatory and physiological responses in nearby target cells via binding to the soluble guanylate cyclase heme moiety. Higher NO concentrations, as synthesized by the inducible NO synthase (iNOS) during inflammatory processes, show additional effects: NO may react with O₂, yielding nitrogen oxides like N₂O₃ that are able to nitrosate thiols. A variety of proteins involved in very different functions of the cell contain cysteine–Zn²⁺ complexes. Effects of NO on different proteins containing cysteine–Zn²⁺ domains and playing essential roles during transcription, protein folding, and proteolysis are discussed. It is suggested that iNOS-derived NO acts as a signal molecule targeting cysteine–Zn²⁺ linkages, thus enabling cells to react toward nitrosative stress.—Kröncke, K.-D. Cysteine–Zn²⁺ complexes: unique molecular switches for inducible nitric oxide synthase-derived NO.

Key Words: chaperone • cysteine switch • metalloproteinase • nitric oxide • transcription • zinc

	INTRODUCTION

TOP ABSTRACT INTRODUCTION TRANSCRIPTION PROTEIN FOLDING PROTEOLYSIS CONCLUSIONS REFERENCES

 
NITRIC OXIDE (NO) synthesized in low concentrations on demand as signal molecule by constitutively expressed endothelial or neuronal NO synthases (eNOS, nNOS) binds to the iron of the heme prosthetic group of soluble guanylate cyclase. This disrupts the plane of the heme iron and induces a conformational change that allosterically activates the enzyme to synthesize the second messenger cGMP, which in turn modulates an array of mediators, including ion channels, phosphodiesterases, and protein kinases. Higher concentrations of NO, however, synthesized by the inducible NO synthase (iNOS) expressed during a variety of inflammatory diseases (for a review, see ref 1 ) will react with oxygen in a third order reaction almost exclusively dependent on the NO concentration leading to reactive nitrogen oxide intermediates (RNOI, NO_x), the most important probably being N₂O₃ (Fig. 1 A). Nitrogen oxides are able to nitrosate cysteine thiols in proteins yielding S-nitrosothiols (R-SNO) (Fig. 1B ), which may result in enzyme activation or inhibition, depending on the functional mechanism of the enzyme. Cysteine thiols are often involved in complexing Zn²⁺ to form zinc finger or similar structures like the treble clef finger or the RING, LIM, B-box, or PHD/LAP domain. All these structures have in common that one or two Zn²⁺ are complexed in a tetrahedral arrangement by cysteine thiols and/or imidazole nitrogen atoms of histidine residues (for reviews, see refs 2 3 4 5 ). Zinc finger domains are essential for protein–DNA or protein–RNA interactions and, consequently, zinc finger structures are found in transcription factors. The other domains mentioned above are thought to primarily mediate protein–protein interactions. These Zn²⁺ complexing sites differ in sequence conservation and 3-dimensional structure. Although there is some resemblance at the amino acid sequence levels between the zinc complexing domains, the LIM domain and the B-box use sequential zinc ligation schemes and the RING and the PHD/LAP domain use cross-brace ligation topologies, which allows the two zinc binding sites to fold into an integrated domain (3 , 4) .

View larger version (14K): [in this window] [in a new window]   Figure 1. Reaction products of NO with O2, the heme moiety, and thiols. (A) NO reacts with molecular oxygen almost exclusively depending on the NO concentration: the higher the concentration of NO, the more likely the reaction of NO with O2 yielding reactive nitrogen oxide intermediates like NO2 or N2O3. Highly reactive intermediate products are in boldface. (B) NO produced by constitutively expressed NO synthases in a tightly regulated fashion resulting in low NO concentrations can bind directly to the iron of protein heme groups in a reversible manner, thus exerting signaling functions. Under conditions of high-output NO synthesis from inducible NO synthase the reaction with O2 will become more likely, and the arising reactive intermediates (NOx) will S-nitrosate thiols.

RNOI or S-nitrosothiols, the latter via a transnitrosation mechanism, are both able to S-nitrosate cysteine thiols involved in Zn²⁺ complexation (6 7 8 9 10) . This leads to disruption of cysteine–Zn²⁺ linkages and disulfide formation (6) , which will induce conformational protein changes. Initially this mechanism was thought to lead to inhibition of transcription factor DNA binding activities (6) , thus being one of the main molecular mechanisms of how NO inhibits gene expression (11 , 12) . However, this simple picture is slowly changing and evidence is accumulating that cysteine–Zn²⁺ linkages represent molecular switches for NO.

The results reviewed in the following have all been obtained using exogenously added NO donors as the source for NO. Of course the question arises, whether these are biological relevant conditions. However, we recently have found that NO synthesized by the iNOS induces intracellular Zn²⁺ release in cytokine-activated endothelial cells (D. Spahl, D. Berendji, V. Kolb-Bachofen, K. D. Kröncke, unpublished observations). This strongly suggests that nitrosative stress induced by iNOS-derived NO will affect cysteine–Zn²⁺ complexes within cells.

	TRANSCRIPTION

TOP ABSTRACT INTRODUCTION TRANSCRIPTION PROTEIN FOLDING PROTEOLYSIS CONCLUSIONS REFERENCES

 
Transcription factors are proteins that bind to responsive elements in promoter or enhancer regions of genes subsequently regulating gene transcription. The most prevalent DNA binding motif of transcription factors is the zinc finger structure (2) . The yeast zinc finger transcription factor LAC9 was the first transcription factor shown to be inhibited by NO (6) . Subsequently, the DNA binding activities of the eukaryotic zinc finger transcription factors Sp1, EGR-1, as well as members of the nuclear receptor superfamily like the vitamin D₃ receptor (VDR) and the retinoid X receptor (RXR) have all been found to be inhibited by NO (11 , 12) . Whether the zinc fingers are of the cys₂his₂-type or the cys₄-type does not appear to play a significant role, as both types are affected by NO. NO-mediated inhibition turned out to be reversible by post-treatment with DTT, suggesting that cells are able to repair zinc finger structures disrupted by NO. Inhibition of DNA binding of the zinc finger transcription factor Sp1 by NO correlates with NO-induced inhibition of IL-1ß-driven IL-2 mRNA expression in lymphocytes (11) and with inhibition of IL-1ß-mediated ICAM-1 mRNA expression in endothelial cells (13) . Experiments with transiently transfected cells showed that NO (with an IC₅₀ value of 1 µM at steady-state concentration) inhibits luciferase activity under the control of vitamin D₃-responsive elements, thus demonstrating NO-induced inhibition of zinc finger-dependent vitamin D₃ signaling in whole cells (12) . These results provide examples of NO-mediated inhibition of zinc finger-dependent gene transcription (Fig. 2 ). However, the opposite may also occur, as has been shown for the tumor necrosis factor (TNF-) gene, where Sp1 acts as a repressor. NO activates the TNF- gene by disrupting DNA binding and thus the repressor activity of Sp1 (14) , a finding that led the authors coin the term ‘NO response element’ for the Sp1-specific consensus sequence.

View larger version (19K): [in this window] [in a new window]   Figure 2. Effects of NO on zinc finger-dependent transcription. If a zinc finger transcription factor acts as a dominant regulating activator of gene transcription, NO-mediated disruption of the zinc fingers inhibits transcription as has been found for the IL-2 (11) and the ICAM-1 gene (13) . In contrast, if a zinc finger transcription factor functions as a repressor, NO-mediated disruption of the zinc fingers will lead to activation of transcription as has been found for the TNF- gene (14) , provided that dominant regulating transcriptional activators of the respective gene are not NO-sensitive. NO may thus inhibit or activate transcription by the same molecular mechanism, depending on the structure of the promotor and on the transcription factors involved.

In conclusion, genes may be turned on or off via reversible disruption of cysteine–Zn²⁺ linkages in transcription factors. Thus, depending on the structure of the promotor and the transcription factors that dominantly regulate the respective gene, iNOS-derived NO represents a powerful tool for regulating gene expression.

	PROTEIN FOLDING

TOP ABSTRACT INTRODUCTION TRANSCRIPTION PROTEIN FOLDING PROTEOLYSIS CONCLUSIONS REFERENCES

 
Most newly synthesized polypeptides depend for efficient folding on interaction with molecular chaperones, many of which are also known as heat shock or stress proteins. Chaperones recognize and bind to nascent polypeptide chains, partially folded intermediates, or denatured proteins to prevent their misfolding and/or aggregation. They are thus involved in proper protein folding, assembly, disassembly, membrane transport, and the protection of cells from effects of heat or other stresses. The eukaryotic heat shock protein (Hsp) 40 or bacterial DnaJ family of chaperones comprises > 100 members that contain several conserved regions representing potential functional domains, one region containing two zinc ions complexed by eight cysteines resembling the RING finger motif (15) . The best-defined role for DnaJ is its action as a cochaperone for the DnaK chaperone. DnaK recognizes and binds extended segments of unfolded polypeptides that are enriched in hydrophobic amino acids, thus preventing their aggregation, whereas DnaJ modulates binding and release of polypeptides from DnaK. The DnaJ RING finger-like domain is required for binding of misfolded protein intermediates and for stabilization of the DnaK–substrate complex (16 , 17) . After pretreatment of DnaJ with NO, the DnaJ/DnaK chaperone activity is inhibited (Fig. 3 ), and this inhibitory effect correlates with S-nitrosation and Zn²⁺ release from DnaJ (10) . In contrast, even very high concentrations of NO do not inhibit the activity of GroEL, a chaperonin without zinc sulfur clusters or cysteines. An Escherichia coli strain dependent for growth on DnaJ/DnaK is more susceptible to the bacteriostatic effect of NO than wild-type bacteria, suggesting that the DnaJ/DnaK system is an important molecular target for NO in whole bacteria (10) . Thus, an encounter of bacterial cells with NO can impair the protein folding activity of this bacterial chaperone system. As Hsp40 is also functional in mammals, these findings suggest that nitrosative stress during inflammatory reactions may alter the efficiency of de novo protein folding as well as proper refolding of misfolded proteins in mammalian cells.

View larger version (15K): [in this window] [in a new window]   Figure 3. Effects of NO on chaperones containing zinc sulfur complexes. The bacterial chaperone DnaJ (homologous to the mammalian Hsp40) is active only with an intact RING finger-like zinc sulfur motif. NO via S-nitrosation and subsequent Zn2+ ejection disrupts this zinc sulfur cluster, thus leading to inactivation of the DnaJ chaperone activity. In contrast, the bacterial chaperone Hsp33 containing an intact single zinc sulfur cluster is an inactive monomer, but disruption of its zinc sulfur domain by oxidative and possibly nitrosative stress leads to disulfide formation, dimerization, and activation of the Hsp33 chaperone function. NO may thus either inhibit or activate chaperones containing zinc sulfur clusters, depending on how these chaperones function.

However, the situation appears to be more complicated, as bacterial Hsp33 has recently been identified as a novel molecular chaperone containing a single cys₄-zinc cluster (18) . In contrast to DnaJ, Hsp33 with an intact zinc sulfur domain is inactive, but disruption of its zinc sulfur cluster by oxidation of the cysteine thiols with H₂O₂ yields disulfides and results in dimerization and activation of its chaperone activity (18 19 20 21) . This fast redox mechanism has been proposed to represent a first line of defense against oxidative stress, but since NO will most likely disrupt the Hsp33 zinc sulfur domain leading to disulfide formation, nitrosative stress will probably result in activation of Hsp33 (Fig. 3) . Whether a possible Hsp33 activation by NO might compensate the NO-mediated inhibition of the DnaJ/DnaK chaperone system remains to be investigated.

In conclusion, NO may either inhibit or activate chaperones containing cysteine–Zn²⁺ clusters via disruption of these domains.

	PROTEOLYSIS

TOP ABSTRACT INTRODUCTION TRANSCRIPTION PROTEIN FOLDING PROTEOLYSIS CONCLUSIONS REFERENCES

 
Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that share common structural and functional elements and are able to cleave one or several extracellular matrix constituents as well as nonmatrix proteins. Ample evidence exists on the role of MMPs in normal and pathological processes including embryogenesis, wound healing, inflammation, and cancer. All known MMPs are synthesized as inactive (latent) proMMPs and require activation via cleavage of a propeptide domain. This propeptide consists of 80–90 amino acids containing a well-conserved cysteine residue and forms a cap over the active MMP site. The catalytically active site contains a zinc ion that is essential for the proteolytic MMP activity, and three histidine residues that coordinate with the catalytic Zn²⁺ are conserved among all MMP family members. A methionine is located beneath the cavity formed by the histidines, providing increased hydrophobicity in this area to enhance the zinc histidine complexation (for a review, see ref 22 ). The latency of the MMPs is due to a complex between the propeptide cysteine and the Zn²⁺ of the catalytic domain complexed by the three histidines (Fig. 4 ). This complex blocks the active site and appears to exclude H₂O, which as the fourth ligand is essential for catalysis, from the Zn²⁺ coordination sphere. Accordingly, when the cysteine is ‘on’ the zinc, activity of the enzyme is ‘off’. This mechanism has been termed ‘cysteine switch’ (23) .

View larger version (13K): [in this window] [in a new window]   Figure 4. NO activates matrix metalloproteinases (MMPs) containing a ‘cysteine switch’ via S-nitrosation. MMPs are secreted as inactive proMMPs containing a propeptide that forms a cap over the active MMP site with a critical cysteine residue providing the fourth coordination ligand to a catalytical zinc ion. NO will S-nitrosate this cysteine residue, thus inducing dissociation of the cysteine–Zn2+ linkage, whereas the Zn2+ complexation by the three histidines is not affected. As a consequence, the MMPs are activated and are now able to degrade appropriate matrix substrates.

Human MMP-8 has been found to be activated by NO under aerobic but not anaerobic conditions, as well as by NO₂, suggesting that RNOI are the species that activate MMP-8 enzyme activity (24) . However, no molecular mechanism has been provided. TNF--converting enzyme (TACE) is a member of a disintegrin and metalloproteinase family, a group of unique transmembrane metalloproteinases with similar propeptide and catalytical domains as found for the MMPs (for a review, see ref 25 ). Zhang et al. recently reported that NO activates TACE in a DTT-reversible manner (26) . They also found that NO induces S-nitrosation of a cysteine in the TACE prodomain that correlates with TACE activation. These findings are consistent with the following molecular mechanism: S-nitrosation of the critical conserved MMP cysteine will induce dissociation of the cysteine–Zn²⁺ linkage leading to replacement of the cysteine ligand by H₂O. As Zn²⁺ complexation by histidine residues is not affected by NO, disruption of the cysteine–Zn²⁺ linkage leads to MMP enzyme activation (Fig. 4) .

	CONCLUSIONS

TOP ABSTRACT INTRODUCTION TRANSCRIPTION PROTEIN FOLDING PROTEOLYSIS CONCLUSIONS REFERENCES

 
Considering the zinc finger motif as a sensitive target of nitrosative and oxidative stress raises the question as to why zinc finger domains have been conserved during evolution as indispensable for DNA binding. However, using one molecular mechanism (i.e., loss of Zn²⁺ from zinc finger domains), it is possible to regulate transcription of a whole set of genes. Thus, at conditions of nitrosative stress, genes that are dominantly regulated by redox-sensitive transcription factors will be turned off and genes that are dominantly regulated by redox-insensitive transcription factors may be selectively transcribed and translated. The opposite may occur if a zinc finger transcription factor acts as a dominant repressor. In other proteins like the MMPs or Hsp33, the Zn²⁺ coordinated by cysteines might play a role in keeping the enzyme in a reduced and inactive form; S-nitrosation is a signal to activate these proteins under conditions of nitrosative stress. Although disruption of zinc sulfur clusters may also inhibit protein activities, as has been found for the alcohol dehydrogenase (27) or for the cochaperone DnaJ, a picture is emerging that the cysteine–Zn²⁺ switch is a molecular target for iNOS-derived NO, thus enabling cells to react toward nitrosative stress.

Received for publication April 17, 2001. Revision received July 31, 2001.

	REFERENCES

TOP ABSTRACT INTRODUCTION TRANSCRIPTION PROTEIN FOLDING PROTEOLYSIS CONCLUSIONS REFERENCES

 

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