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

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: I...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2010-12, Vol.107 (49), p.20974-20979
Main Authors: Diao, Yarui, Liu, Wei, Wong, Catherine C. L., Wang, Xi, Lee, Kaman, Cheung, Po-yan, Pan, Lifeng, Xu, Tao, Han, Jiahuai, Yates, John R., Zhang, Mingjie, Wu, Zhenguo, Cobb, Melanie H.
Format: Article
Language:English
Subjects:
Adenosine triphosphatase
Adenosine Triphosphate - metabolism
Adipocytes
Animal social behavior
Biochemistry
Biological Sciences
Chemical bonds
Cysteine - metabolism
Disulfides
Disulfides - metabolism
HeLa cells
Humans
Kinases
MAP Kinase Kinase 6 - antagonists & inhibitors
MAP Kinase Kinase 6 - metabolism
Mitogen-Activated Protein Kinase Kinases - metabolism
Oxidation
Oxidation-Reduction
Oxidative stress
Phosphatases
Physiological regulation
Protein Binding
Proteins
Thiols
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1007225107