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Oxidation-induced intramolecular disulfide bond inactivates mitogen-activated protein kinase kinase 6 by inhibiting ATP binding

descriptionPublicationkeyboard_double_arrow_right Article 15 Nov 2010 China (People's Republic of) English Publisher:Proceedings of the National Academy of SciencesJournal:Proceedings of the National Academy of Sciences, volume 107, pages 20,974-20,979 (issn: 0027-8424, eissn: 1091-6490,

Authors: Diao, Yarui; Liu, Wei; Wong, Catherine C.L.; Wang, Xi; Lee, Ka Man; Cheung, Po Yan; Pan, Lifeng; +5 Authors

doi: 10.1073/pnas.1007225107

pmid: 21078955

pmc: PMC3000308

Oxidation-induced intramolecular disulfide bond inactivates mitogen-activated protein kinase kinase 6 by inhibiting ATP binding

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Abstract

Mitogen-activated protein kinase kinase 6 (MKK6) is a member of the mitogen-activated protein kinase (MAPK) kinase (MAP2K) subfamily that specifically phosphorylates and activates the p38 MAPKs. Based on both biochemical and cellular assays, we found that MKK6 was extremely sensitive to oxidation: It was inactivated by oxidation and its kinase activity was fully restored upon treatment with a reducing agent. Detailed mechanistic studies showed that cysteines 109 and 196, two of the six cysteines in MKK6, formed an intramolecular disulfide bond upon oxidation that inactivated MKK6 by inhibiting its ATP binding. This mechanism is distinct from that seen in other redox-sensitive kinases. The two cysteines involved in intramolecular disulfide formation are conserved in all seven members of the MAP2K family. Consistently, we confirmed that other MAP2Ks were also sensitive to oxidation. Our work reveals that MKK6 and other MAP2Ks are a distinct class of cellular redox sensors.

Country

China (People's Republic of)

Related Organizations

State Key Laboratory of Neuroscience
China (People's Republic of)
Hong Kong University of Science and Technology (香港科技大學)
China (People's Republic of)
Xiamen University
China (People's Republic of)
Scripps Research Institute
United States
Hong Kong Polytechnic University
China (People's Republic of)

Keywords

Mitogen-Activated Protein Kinase Kinases, REDOX REGULATION, STRESS, 571, CYSTEINE OXIDATION, TYROSINE-PHOSPHATASE 1B, PATHWAYS, 500, MAP Kinase Kinase 6, MAP KINASE, MECHANISMS, HYDROGEN-PEROXIDE, Adenosine Triphosphate, DISCOVERY, Humans, JNK, Cysteine, Disulfides, Oxidation-Reduction, Protein Binding

7 Research products, page 1 of 1

Dual specificity mitogen-activated protein kinase kinase 6
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MAP kinase kinase 6c
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Uncharacterized protein
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Map kinase kinase
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