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Cellular Redox Profiling Using High-content Microscopy
Published on: May 14, 2017
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An isomerase completes the circuit for a redox switch.
1Departamento de Biociencias, Facultad de Química, Universidad de la República, Montevideo 11800, Uruguay; Institut Pasteur de Montevideo, Mataojo 2020, Montevideo 11400, Uruguay.
The Journal of Biological Chemistry
|February 25, 2018
Summary
Human transglutaminase 2 (TG2) activity is regulated by a redox switch. Khosla and colleagues discovered that ERp57 oxidatively inactivates TG2, revealing a new target for inhibiting TG2 in disease.
Area of Science:
- Biochemistry
- Molecular Biology
- Enzymology
Background:
- Human transglutaminase 2 (TG2) catalyzes protein cross-linking via glutamine and lysine residues.
- TG2 activity is modulated by an allosteric disulfide bond, but the formation mechanism was unclear.
- Oxidative cysteine modifications regulate many biological systems, but specific mechanisms are often unknown.
Purpose of the Study:
- To elucidate the mechanism of TG2 inactivation via oxidative modifications.
- To identify the specific protein responsible for forming the regulatory disulfide bond in TG2.
- To explore potential therapeutic strategies targeting TG2 activity in pathological conditions.
Main Methods:
- Investigated the interaction between human transglutaminase 2 (TG2) and protein disulfide isomerase ERp57.
- Utilized biochemical assays to monitor TG2 activity and disulfide bond formation.
- Analyzed the redox state of cysteine residues in TG2 upon interaction with ERp57.
Main Results:
- Demonstrated that ERp57 oxidatively inactivates TG2.
- Showed that this inactivation involves the formation of a specific disulfide bond in TG2.
- Identified this interaction as the first example of a defined, reversible protein-controlled redox switch.
Conclusions:
- ERp57 acts as a key regulator of TG2 activity through oxidative inactivation.
- The TG2-ERp57 interaction represents a novel redox switch mechanism.
- Targeting this interaction offers new strategies for inhibiting aberrant TG2 activity in diseases.
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