The catalytic activity of TCPTP is auto-regulated by its intrinsically disordered tail and activated by Integrin alpha-1
Jai Prakash Singh,
Yang Li,
Yi-Yun Chen,
Shang-Te Danny Hsu,
Rebecca Page,
Wolfgang Peti () and
Tzu-Ching Meng ()
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Jai Prakash Singh: Institute of Biological Chemistry, Academia Sinica
Yang Li: University of Connecticut Health Center
Yi-Yun Chen: Institute of Biological Chemistry, Academia Sinica
Shang-Te Danny Hsu: Institute of Biological Chemistry, Academia Sinica
Rebecca Page: University of Connecticut Health Center
Wolfgang Peti: University of Connecticut Health Center
Tzu-Ching Meng: Institute of Biological Chemistry, Academia Sinica
Nature Communications, 2022, vol. 13, issue 1, 1-12
Abstract:
Abstract T-Cell Protein Tyrosine Phosphatase (TCPTP, PTPN2) is a non-receptor type protein tyrosine phosphatase that is ubiquitously expressed in human cells. TCPTP is a critical component of a variety of key signaling pathways that are directly associated with the formation of cancer and inflammation. Thus, understanding the molecular mechanism of TCPTP activation and regulation is essential for the development of TCPTP therapeutics. Under basal conditions, TCPTP is largely inactive, although how this is achieved is poorly understood. By combining biomolecular nuclear magnetic resonance spectroscopy, small-angle X-ray scattering, and chemical cross-linking coupled with mass spectrometry, we show that the C-terminal intrinsically disordered tail of TCPTP functions as an intramolecular autoinhibitory element that controls the TCPTP catalytic activity. Activation of TCPTP is achieved by cellular competition, i.e., the intrinsically disordered cytosolic tail of Integrin-α1 displaces the TCPTP autoinhibitory tail, allowing for the full activation of TCPTP. This work not only defines the mechanism by which TCPTP is regulated but also reveals that the intrinsically disordered tails of two of the most closely related PTPs (PTP1B and TCPTP) autoregulate the activity of their cognate PTPs via completely different mechanisms.
Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27633-6
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DOI: 10.1038/s41467-021-27633-6
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