Sts (suppressor of T-cell receptor signalling)-1 and Sts-2 are HPs (histidine phosphatases) that negatively regulate TCR (T-cell receptor) signalling pathways, including those involved in cytokine production. HPs play key roles in such varied biological processes as metabolism, development and intracellular signalling. They differ considerably in their primary sequence and substrate specificity, but possess a catalytic core formed by an invariant quartet of active-site residues. Two histidine and two arginine residues cluster together within the HP active site and are thought to participate in a two-step dephosphorylation reaction. To date there has been little insight into any additional residues that might play an important functional role. In the present study, we identify and characterize an additional residue within the Sts phosphatases (Sts-1 Arg383 or Sts-2 Arg369) that is critical for catalytic activity and intracellular function. Mutation of Sts-1 Arg383 to an alanine residue compromises the enzyme's activity and renders Sts-1 unable to suppress TCR-induced cytokine induction. Of the multiple amino acids substituted for Arg383, only lysine partially rescues the catalytic activity of Sts-1. Although Sts-1 Arg383 is conserved in all Sts homologues, it is only conserved in one of the two sub-branches of HPs. The results of the present study highlight an essential role for Sts-1 phosphatase activity in regulating T-cell activation and add a new dimension of complexity to our understanding of HP catalytic activity.
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Research Article|
June 13 2013
New insights into the catalytic mechanism of histidine phosphatases revealed by a functionally essential arginine residue within the active site of the Sts phosphatases
Boris San Luis
;
Boris San Luis
*Department of Molecular Genetics and Microbiology, Room 130, Life Sciences Building, Stony Brook University, Stony Brook, NY 11794-5222, U.S.A.
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Nicolas Nassar
;
Nicolas Nassar
†Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, MLC 7013, 3333 Burnet Avenue, Cincinnati, OH 45229, U.S.A.
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Nick Carpino
Nick Carpino
1
*Department of Molecular Genetics and Microbiology, Room 130, Life Sciences Building, Stony Brook University, Stony Brook, NY 11794-5222, U.S.A.
1To whom correspondence should be addressed (email nicholas.carpino@stonybrook.edu).
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Biochem J (2013) 453 (1): 27–35.
Article history
Received:
November 21 2012
Revision Received:
April 05 2013
Accepted:
April 09 2013
Accepted Manuscript online:
April 09 2013
Citation
Boris San Luis, Nicolas Nassar, Nick Carpino; New insights into the catalytic mechanism of histidine phosphatases revealed by a functionally essential arginine residue within the active site of the Sts phosphatases. Biochem J 1 July 2013; 453 (1): 27–35. doi: https://doi.org/10.1042/BJ20121769
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