1. Structural Biology Laboratory and,
2. Protein Analysis Laboratory, The London Research Institute, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
3. School of Crystallography, Birkbeck College, Malet Street, London WC1E 7HX, UK
4. Cancer Research UK, Stress Response Laboratory, Biomedical Research Centre, Ninewells Hospital, Dundee DD1 9SY, UK
5. Division of Gene Regulation and Expression, College of Life Sciences, MSI/WTB Complex, University of Dundee, Dundee DD1 5EH, UK
6. These authors contributed equally to this work.
7. Present address: ESRF, 6 Rue Jules Horowitz, 38043 Grenoble, Cedex 9, France.

Correspondence to: N. Q. McDonald^1,3 Correspondence and requests for materials should be addressed to N.Q.M. (Email: neil.mcdonald@cancer.org.uk).

Abstract

Reactive oxygen species trigger cellular responses by activation of stress-responsive mitogen-activated protein kinase (MAPK) signalling pathways^{1, 2}. Reversal of MAPK activation requires the transcriptional induction of specialized cysteine-based phosphatases that mediate MAPK dephosphorylation³. Paradoxically, oxidative stresses generally inactivate cysteine-based phosphatases by thiol modification and thus could lead to sustained or uncontrolled MAPK activation^{4, 5}. Here we describe how the stress-inducible MAPK phosphatase, Sdp1, presents an unusual solution to this apparent paradox by acquiring enhanced catalytic activity under oxidative conditions. Structural and biochemical evidence reveals that Sdp1 employs an intramolecular disulphide bridge and an invariant histidine side chain to selectively recognize a tyrosine-phosphorylated MAPK substrate. Optimal activity critically requires the disulphide bridge, and thus, to the best of our knowledge, Sdp1 is the first example of a cysteine-dependent phosphatase that couples oxidative stress with substrate recognition. We show that Sdp1, and its paralogue Msg5, have similar properties and belong to a new group of phosphatases unique to yeast and fungal taxa.

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