title: Oxidation-induced intramolecular disulfide bond inactivates mitogen-activated protein kinase kinase 6 by inhibiting ATP binding.
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.
authors.affiliation: Department of Biochemistry, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, China.
authors.forename: Yarui
authors.initials: Y
authors.lastname: Diao
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Catherine C L
authors.initials: CC
authors.lastname: Wong
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.forename: Kaman
authors.initials: K
authors.lastname: Lee
authors.forename: Po-yan
authors.initials: PY
authors.lastname: Cheung
authors.forename: Lifeng
authors.initials: L
authors.lastname: Pan
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.forename: Jiahuai
authors.initials: J
authors.lastname: Han
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Mingjie
authors.initials: M
authors.lastname: Zhang
authors.forename: Zhenguo
authors.initials: Z
authors.lastname: Wu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D003545:Cysteine / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism*; D006801:Humans; D048669:MAP Kinase Kinase 6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010084:Oxidation-Reduction; D011485:Protein Binding
chemical_list: D004220:Disulfides; D000255:Adenosine Triphosphate; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D003545:Cysteine