A highly conserved redox-active Mx(2)CWx(6)R motif regulates Zap70 stability and activity.

2.50
Hdl Handle:
http://hdl.handle.net/10033/621080
Title:
A highly conserved redox-active Mx(2)CWx(6)R motif regulates Zap70 stability and activity.
Authors:
Thurm, Christoph; Poltorak, Mateusz P; Reimer, Elisa; Brinkmann, Melanie M; Leichert, Lars; Schraven, Burkhart; Simeoni, Luca
Abstract:
ζ-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.
Affiliation:
Helmholtz Centre of infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Citation:
A highly conserved redox-active Mx(2)CWx(6)R motif regulates Zap70 stability and activity. 2017, 8 (19):30805-30816 Oncotarget
Journal:
Oncotarget
Issue Date:
9-May-2017
URI:
http://hdl.handle.net/10033/621080
DOI:
10.18632/oncotarget.16486
PubMed ID:
28415650
Type:
Article
Language:
en
ISSN:
1949-2553
Appears in Collections:
junior research group immunomodulation (VIMM); publications of the department of immune control (IMMK)

Full metadata record

DC FieldValue Language
dc.contributor.authorThurm, Christophen
dc.contributor.authorPoltorak, Mateusz Pen
dc.contributor.authorReimer, Elisaen
dc.contributor.authorBrinkmann, Melanie Men
dc.contributor.authorLeichert, Larsen
dc.contributor.authorSchraven, Burkharten
dc.contributor.authorSimeoni, Lucaen
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.en
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
This item is licensed under a Creative Commons License
Creative Commons
All Items in HZI are protected by copyright, with all rights reserved, unless otherwise indicated.