Multiple Mechanisms of Zinc-Mediated Inhibition for the Apoptotic Caspases-3, -6, -7, and -8
| Autor: | Jeanne A. Hardy, Kevin B. Dagbay, Scott J. Eron, Derek J. MacPherson |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Zinc binding chemistry.chemical_element Apoptosis Zinc Biochemistry Article 03 medical and health sciences 0302 clinical medicine Humans Inhibition constant Caspase biology Extramural General Medicine Cell biology 030104 developmental biology chemistry Apoptotic cell death Caspases biology.protein Molecular Medicine 030217 neurology & neurosurgery Intracellular |
| Zdroj: | ACS chemical biology. 13(5) |
| ISSN: | 1554-8937 |
| Popis: | Zinc is emerging as a widely used and important biological regulatory signal. Cellular zinc levels are tightly regulated by a complex array of zinc importer and exporters to control processes such as apoptotic cell death. While caspase inhibition by zinc has been reported previously, the reported inhibition constants were too weak to suggest a critical biological role for zinc-mediated inhibition. In this work we have adopted a method of assessing available zinc. This allowed assessment of the accurate inhibition constants for apoptotic caspases, caspase-3, -6, -7 and -8. Each of these caspases are inhibited by zinc at intracellular levels, however, with widely differing inhibition constants and different zinc binding stoichiometries. Caspase -3, -6 and -8 appear to be constitutively inhibited by typical zinc levels and this inhibition must be lifted to allow activation. The inhibition constant for caspase-7 (76 nM) is much weaker than for the other apoptotic caspases (2.6–6.9 nM) suggesting that caspase-7 is not inactivated by normal zinc concentrations but can be inhibited under conditions of zinc stress. Caspase-3, -7, and -8 were found to bind three, one, and two zincs respectively. In each of these caspases, zinc was present in the active site, in contrast to caspase-6, which binds one zinc allosterically. The most notable new mechanism to emerge from this work is for zinc-mediated inhibition of caspase-8. Zinc binds caspase-8 directly at the active site and at a second site. Zinc binding inhibits formation of the caspase-8 dimer, the activated form of the enzyme. Together these findings suggest that zinc plays a critical role in regulation of apoptosis by direct inactivation of caspases, in a manner that is unique for each caspase. |
| Databáze: | OpenAIRE |
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