A1 Refereed original research article in a scientific journal
The Interaction Mechanism of Intrinsically Disordered PP2A Inhibitor Proteins ARPP-16 and ARPP-19 With PP2A
Authors: Thapa Chanda, Roivas Peikka, Haataja Tatu, Permi Perttu, Pentikainen Ulla
Publisher: FRONTIERS MEDIA SA
Publishing place: Lausanne
Publication year: 2021
Journal: Frontiers in Molecular Biosciences
Journal name in source: FRONTIERS IN MOLECULAR BIOSCIENCES
Journal acronym: FRONT MOL BIOSCI
Article number: ARTN 650881
Volume: 8
Number of pages: 16
eISSN: 2296-889X
DOI: https://doi.org/10.3389/fmolb.2021.650881
Web address : https://doi.org/10.3389/fmolb.2021.650881
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/57557884
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.
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