Zinc Coordination Environments in Proteins as Redox Sensors and Signal Transducers

Abstract

Zinc/cysteine coordination environments in proteins are redox-active. Oxidation of the sulfur ligands mobilizes zinc, while reduction of the oxidized ligands enhances zinc binding, providing redox control over the availability of zinc ions. Some zinc proteins are redox sensors, in which zinc release is coupled to conformational changes that control varied functions such as enzymatic activity, binding interactions, and molecular chaperone activity. Whereas the released zinc ion in redox sensors has no known function, the redox signal is transduced to specific and sensitive zinc signals in redox transducers. Released zinc can bind to sites on other proteins and modulate signal transduction, generation of metabolic energy, mitochondrial function, and gene expression. The paradigm of such redox transducers is the zinc protein metallothionein, which, together with its apoprotein, thionein, functions at a central node in cellular signaling by redistributing cellular zinc, presiding over the availability of zinc, and interconverting redox and zinc signals. In this regard, the transduction of nitric oxide (NO) signals into zinc signals by metallothionein has received particular attention. It appears that redox-inert zinc has been chosen to control some aspects of cellular thiol/disulfide redox metabolism. Tight control of zinc is essential for redox homeostasis because both increases and decreases of cellular zinc elicit oxidative stress. Depending on its availability, zinc can be cytoprotective as a pro-antioxidant or cytotoxic as a pro-oxidant. Any condition with acute or chronic oxidative stress is expected to perturb zinc homeostasis.

Redox‐dependent disulfide bond formation in SAP30L corepressor protein: Implications for structure and function

“…A total of 22 specific tryptic peptides were identified in these conditions, accounting for 100% sequence coverage (Table II). No disulfidecontaining peptides were detected, including the tryptic peptide [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] with adjacent cysteine residues. Yet, formation of intramolecular disulfide bonds were observed after a short-term storage, even in reducing conditions, indicating that an oxidized form is favored in small tryptic peptides having free thiol groups.…”

“…This peptide was further subjected to ECD-MS/MS measurement, proving that the disulfide bond is, indeed, formed between the two adjacent cysteinyl residues (i.e., a vicinal disulfide). The ECD spectrum of [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] 21 ion showed multiple z-ions up to the formed disulfide bond (Supporting Information Fig. S5).…”

“…All peptides containing free cysteines were absent, indicating that the disulfide bonds are formed before digestion and oxidation does not occur at low pH. Five of the peptides were identified to contain disulfide bonds; the peptides [1][2][3][4][5][6][7][8][9][10][11][12][13] and confirmed again the vicinal disulfide bond between the adjacent Cys29 and Cys30, while the three larger disulfide-linked peptides confirmed the other disulfide bond between Cys38 and Cys74. Therefore, it seems that pepsin could be preferred over trypsin for identifying redox-active disulfide bonds in proteins since even in the absence of a reducing agent, no auto-oxidation or mixed disulfide bonds were observed following digestion.…”

“…[1][2][3][4] Many eukaryotic proteins utilize zinc finger (ZnF) motifs with reactive cysteine residues as redox switches to sense changes in cellular redox potential by reversible disulfide bond formation or other oxidative modifications. These modifications may induce conformational changes, which in turn affect protein activities.…”

“…6 ZnF-based redox switches are involved in many physiological events such as cell growth and differentiation, transcription, translation, signal transduction, and apoptosis. [1][2][3][4] For example, it has been shown that redox-dependent modifications in histone deacetylases (HDACs) can directly affect their transcriptional repression function, most likely involving ZnF motifs. 7,8 Sin3A-associated protein 30-like (SAP30L) is one of the key proteins in a multi-subunit protein complex, which is involved in transcriptional regulation through histone deacetylation.…”