A1 Journal article (refereed)
The Interaction Mechanism of Intrinsically Disordered PP2A Inhibitor Proteins ARPP-16 and ARPP-19 With PP2A (2021)

Thapa, C., Roivas, P., Haataja, T., Permi, P., & Pentikäinen, U. (2021). The Interaction Mechanism of Intrinsically Disordered PP2A Inhibitor Proteins ARPP-16 and ARPP-19 With PP2A. Frontiers in Molecular Biosciences, 8, Article 650881. https://doi.org/10.3389/fmolb.2021.650881

JYU authors or editors

Publication details

All authors or editors: Thapa, Chandan; Roivas, Pekka; Haataja, Tatu; Permi, Perttu; Pentikäinen, Ulla

Journal or series: Frontiers in Molecular Biosciences

eISSN: 2296-889X

Publication year: 2021

Publication date: 26/03/2021

Volume: 8

Article number: 650881

Publisher: Frontiers Media SA

Publication country: Switzerland

Publication language: English

DOI: https://doi.org/10.3389/fmolb.2021.650881

Publication open access: Openly available

Publication channel open access: Open Access channel

Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/74917

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.

Keywords: proteins; NMR spectroscopy; cancer cells; cell signaling

Free keywords: intrinsically disordered proteins; NMR spectroscopy; SAXS; PP2A; protein-protein interaction; PP2A inhibitor proteins

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Ministry reporting: Yes

Reporting Year: 2021

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