Redox Regulation of Inflammatory Processes Is Enzymatically Controlled

Figure 5

Thiol switch in ADAM17. (a) (1) ADAM17 is active within lipid rafts (blue line). (2) Different stimuli induce the exposure of phosphatidylserine (yellow stars), that interacts with the open and active conformation of the MPD. (3) This process allows ADAM17 to bind and (4) release substrates from the cell surface, for example, soluble interleukin 6 (sIL-6R). (5) Reduced extracellular protein disulfide isomerase PDIA6 catalyzes the disulfide isomerisation targeting the open MPD. (6) The resulting close and inactive structure of ADAM17 is not able to bind and process its substrates. (7) Membrane bound TNFα (mTNFα) is another substrate of ADAM17, (8) which is released upon activation of ADAM17 and also promotes immune response and inflammation. (b) Primary structure of the MPD of human ADAM17, indicating the disulfide bridges involved in the thiol switch. The linear pattern (C₆₀₀–C₆₃₀, C₆₃₅–C₆₄₀) constitutes the active, the overlaying pattern (C₆₀₀–C₆₃₅, C₆₃₀–C₆₄₀), the inactive conformation. (c) Structural consequence of the thiol switch of ADAM17. The red-colored part is highly flexible in the open MPD and therefore not visible in the NMR data. The right structure represents the closed conformation of ADAM17 solved by NMR, in which the red part is packed tightly to the upper, green colored part of the MPD.

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