scholarly journals Thiol-Dependent Recovery of Catalytic Activity from Oxidized Protein Tyrosine Phosphatases

Biochemistry ◽  
2013 ◽  
Vol 52 (37) ◽  
pp. 6412-6423 ◽  
Author(s):  
Zachary D. Parsons ◽  
Kent S. Gates
Keyword(s):  
Catalytic Activity ◽  
Protein Tyrosine Phosphatases ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine

scholarly journals Modulation of Catalytic Activity in Multi-Domain Protein Tyrosine Phosphatases

PLoS ONE ◽  
2011 ◽  
Vol 6 (9) ◽  
pp. e24766 ◽  
Author(s):  
Lalima L. Madan ◽  
S. Veeranna ◽  
Khader Shameer ◽  
Chilamakuri C. S. Reddy ◽  
R. Sowdhamini ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Protein Tyrosine Phosphatases ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Domain Protein

scholarly journals The receptor PTPRU is a redox sensitive pseudophosphatase

2019 ◽  
Author(s):  
Iain M. Hay ◽  
Gareth W. Fearnley ◽  
Pablo Rios ◽  
Maja Köhn ◽  
Hayley J. Sharpe ◽  
...  
Keyword(s):  
Catalytic Activity ◽  
Cell Adhesion ◽  
Tyrosine Phosphorylation ◽  
Catalytic Mechanism ◽  
Protein Tyrosine Phosphatases ◽  
Protein Tyrosine Phosphorylation ◽  
Tyrosine Phosphatases ◽  
Post Translational Modification ◽  
Critical Feature ◽  
Protein Tyrosine

ABSTRACTThe dynamic regulation of protein tyrosine phosphorylation is a critical feature of intercellular communication and is regulated by the actions of kinases and phosphatases. The receptor-linked protein tyrosine phosphatases (RPTPs) are key signaling molecules that possess an extracellular domain and intracellular phosphatase domains. Most human RPTPs have tandem intracellular tyrosine phosphatase domains: a catalytically active membrane proximal (D1) domain; and a membrane distal (D2) inactive “pseudophosphatase” domain. The receptor PTPRU plays a role in development, multiple cancers and has been implicated in the dephosphorylation of cell adhesion proteins. However, PTPRU has a non-canonical D1 domain containing several sequence variations in key catalytic loops that suggest it may function using a mechanism distinct from related RPTPs. Here, we demonstrate through biochemical and structural studies that PTPRU is unique amongst the RPTPs in possessing two pseudophosphatase domains. We show that PTPRU-D1 displays no detectable catalytic activity against a range of phosphorylated substrates and determine that this is due to substantial disorder in the substrate-binding pocket as well as rearrangement of the catalytic loop such that the active site cysteine is occluded. We also show that this cysteine can form an intramolecular disulfide bond with a vicinal “backdoor” cysteine. Further, we demonstrate that the PTPRU D2 domain can recruit substrates of related RPTPs suggesting that this pseudophosphatase functions by competing with active phosphatases for the binding of substrates involved in cell adhesion. Therefore, PTPRU is a bona-fide pseudophosphatase and its functional role in cell signaling is via a non-catalytic mechanism.SIGNIFICANCE STATEMENTProtein tyrosine phosphorylation is a key post-translational modification required for cellular communication that is dynamically regulated by the activities of tyrosine kinases and phosphatases. Receptor tyrosine phosphatases (RPTPs) possess an extracellular receptor domain and intracellular phosphatase domains. We show that PTPRU is a non-canonical RPTP devoid of catalytic activity and demonstrate that this is due to multiple structural rearrangements. Despite this, PTPRU retains the capacity to bind the substrates of related phosphatases suggesting that the non-catalytic function of this pseudophosphatase is to compete with active phosphatases for the binding of substrates. Such pseudoenzymes represent an exciting and growing area of research with implications as key regulators of signaling networks.

Sign in / Sign up

Export Citation Format

Share Document