Abstract
Protein phosphatase 2A (PP2A) activity is critical for maintaining normal physiological cellular functions. PP2A is inhibited by endogenous inhibitor proteins in several pathological conditions including cancer. A PP2A inhibitor protein, ARPP-19, has recently been connected to several human cancer types. Accordingly, the knowledge about ARPP-19—PP2A inhibition mechanism is crucial for the understanding the disease development and the therapeutic targeting of ARPP-19—PP2A. Here, we show the first structural characterization of ARPP-19, and its splice variant ARPP-16 using NMR spectroscopy, and SAXS. The results reveal that both ARPP proteins are intrinsically disordered but contain transient secondary structure elements. The interaction mechanism of ARPP-16/19 with PP2A was investigated using microscale thermophoresis and NMR spectroscopy. Our results suggest that ARPP—PP2A A-subunit interaction is mediated by linear motif and has modest affinity whereas, the interaction of ARPPs with B56-subunit is weak and transient. Like many IDPs, ARPPs are promiscuous binders that transiently interact with PP2A A- and B56 subunits using multiple interaction motifs. In summary, our results provide a good starting point for future studies and development of therapeutics that block ARPP-PP2A interactions.
Highlights
Protein phosphorylation is a dynamic process regulating the functionalities of proteins involved in many cell signaling processes
The main objective of the present work is the structural characterization of ARPP-16 and ARPP-19 and the determination of the regions in ARPP proteins that are involved in binding to phosphatase 2A (PP2A)
The inhibition of the PP2A activity has been shown to promote malignant transformation in human cancer cells as PP2A inhibition results in hyperphosphorylation of large number of oncogenic drivers
Summary
Protein phosphorylation is a dynamic process regulating the functionalities of proteins involved in many cell signaling processes. The equilibrium of protein phosphorylation is achieved through opposing activities of protein kinases and phosphatases. Protein phosphatase 2A (PP2A) is one of the major cellular Serine/Threonine phosphatases. Its proper activity is critical for maintaining normal physiological cellular functions. PP2A inhibition has been observed to contribute to pathogenesis in many diseases such as cancer, cardiovascular disease, diabetes, neurodegenerative disease (e.g., Alzheimer’s and Parkinson’s disease), and developmental conditions involving intellectual disability (Mazhar et al, 2019). The understanding of Protein Mediated PP2A Inhibition Mechanism the PP2A inhibition mechanism and the therapeutic targeting of PP2A has become a tempting area of research with promising potential for clinical impact
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