Preferential redox regulation of cysteine-based protein tyrosine phosphatases: structural and biochemical diversity

Author(s)

Netto, Luis Eduardo S. ; Machado, Luciana Elena S. F.

• Document type: Journal article
• Source: FEBS Journal; v. 289, n. 18, p. 25-pg., 2022-05-11.

Abstract

Protein phosphorylation is a major post-translational modification involved in cell signalling that regulates many physiological and pathological processes. Despite their biological importance, protein phosphatases are less studied than protein kinases. Importantly, the activity of Cys-based protein tyrosine phosphatases (PTPs) can be regulated by reversible oxidation. The initial two-electron oxidation product of the active site Cys is a sulfenic acid (Cys-SOH) that can then undergo distinct outcomes, such as the disulfide bond or a sulfenyl amide formation. Here, we review the biochemical and structural features of PTPs to find patterns that might specify their oxidation products, aiming to get insights into redox regulatory mechanisms. Initially, the structure and biochemistry of PTP1B is presented. Then, we describe structural aspects that are relevant for substrate recognition and catalysis. Notably, all PTPs contain critical Cys residues for the catalysis of dephosphorylation that is prone to oxidative inactivation, which are frequently found oxidized in cells under physiological conditions, such as upon growth factor stimuli. However, direct oxidations of Cys residues in PTPs by H2O2 are rather slow. Therefore, we discuss possible mechanisms that may account for this apparent contradiction between biological and chemical redox aspects of PTPs. Furthermore, we performed a systematic analysis of the distance between active site cysteine and its backdoor cysteine with the attempt to analyse the preference between disulfide bond formation or sulfenyl amide interaction upon oxidation. In summary, PTPs have been showing many possibilities to auto-protect from irreversible oxidation, which is important for cell signalling regulation. (AU)

• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 19/02605-3 - Structural and functional characterization of mitochondrial protein phosphatases by redox metabolism and their role in cell biology
• Grantee: Luciana Elena de Souza Fraga Machado
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 20/10168-0 - Structural and functional characterization of mitochondrial protein phosphatases by redox metabolism and their role in cell biology
• Grantee: Luciana Elena de Souza Fraga Machado
• Support Opportunities: Scholarships in Brazil - Young Researchers