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dc.contributor.authorThurm, Christoph
dc.contributor.authorPoltorak, Mateusz P
dc.contributor.authorReimer, Elisa
dc.contributor.authorBrinkmann, Melanie M
dc.contributor.authorLeichert, Lars
dc.contributor.authorSchraven, Burkhart
dc.contributor.authorSimeoni, Luca
dc.date.accessioned2017-08-30T11:18:03Z
dc.date.available2017-08-30T11:18:03Z
dc.date.issued2017-05-09
dc.identifier.citationA highly conserved redox-active Mx(2)CWx(6)R motif regulates Zap70 stability and activity. 2017, 8 (19):30805-30816 Oncotargeten
dc.identifier.issn1949-2553
dc.identifier.pmid28415650
dc.identifier.doi10.18632/oncotarget.16486
dc.identifier.urihttp://hdl.handle.net/10033/621080
dc.description.abstractζ-associated protein of 70 kDa (Zap70) is crucial for T-cell receptor (TCR) signaling. Loss of Zap70 in both humans and mice results in severe immunodeficiency. On the other hand, the expression of Zap70 in B-cell malignancies correlates with the severity of the disease. Because of its role in immune-related disorders, Zap70 has become a therapeutic target for the treatment of human diseases. It is well-established that the activity/expression of Zap70 is regulated by post-translational modifications of crucial amino acids including the phosphorylation of tyrosines and the ubiquitination of lysines. Here, we have investigated whether also oxidation of cysteine residues regulates Zap70 functions. We have identified C575 as a major sulfenylation site of Zap70. A C575A substitution results in protein instability, reduced activity, and increased dependency on the Hsp90/Cdc37 chaperone system. Indeed, Cdc37 overexpression reconstituted partially the expression but fully the function of Zap70C575A. C575 lies within a Mx(2)CWx(6)R motif which is highly conserved among almost all human tyrosine kinases. Mutation of any of the conserved amino acids, but not of a non-conserved residue preceding the cysteine, also results in Zap70 instability. Collectively, we have identified a new redox-active motif which is crucial for the regulation of Zap70 stability/activity. We believe that this motif has the potential to become a novel target for the development of therapeutic tools to modulate the expression/activity of kinases.
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleA highly conserved redox-active Mx(2)CWx(6)R motif regulates Zap70 stability and activity.en
dc.typeArticleen
dc.contributor.departmentHelmholtz Centre of infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.en
dc.identifier.journalOncotargeten
refterms.dateFOA2018-06-13T05:25:16Z
html.description.abstractζ-associated protein of 70 kDa (Zap70) is crucial for T-cell receptor (TCR) signaling. Loss of Zap70 in both humans and mice results in severe immunodeficiency. On the other hand, the expression of Zap70 in B-cell malignancies correlates with the severity of the disease. Because of its role in immune-related disorders, Zap70 has become a therapeutic target for the treatment of human diseases. It is well-established that the activity/expression of Zap70 is regulated by post-translational modifications of crucial amino acids including the phosphorylation of tyrosines and the ubiquitination of lysines. Here, we have investigated whether also oxidation of cysteine residues regulates Zap70 functions. We have identified C575 as a major sulfenylation site of Zap70. A C575A substitution results in protein instability, reduced activity, and increased dependency on the Hsp90/Cdc37 chaperone system. Indeed, Cdc37 overexpression reconstituted partially the expression but fully the function of Zap70C575A. C575 lies within a Mx(2)CWx(6)R motif which is highly conserved among almost all human tyrosine kinases. Mutation of any of the conserved amino acids, but not of a non-conserved residue preceding the cysteine, also results in Zap70 instability. Collectively, we have identified a new redox-active motif which is crucial for the regulation of Zap70 stability/activity. We believe that this motif has the potential to become a novel target for the development of therapeutic tools to modulate the expression/activity of kinases.


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