A1 Journal article – refereed

The Interaction Mechanism of Intrinsically Disordered PP2A Inhibitor Proteins ARPP-16 and ARPP-19 With PP2A




List of Authors: Thapa Chanda, Roivas Peikka, Haataja Tatu, Permi Perttu, Pentikainen Ulla

Publisher: FRONTIERS MEDIA SA

Place: Lausanne

Publication year: 2021

Journal: Frontiers in Molecular Biosciences

Journal name in source: FRONTIERS IN MOLECULAR BIOSCIENCES

Journal acronym: FRONT MOL BIOSCI

Volume number: 8

Number of pages: 16

eISSN: 2296-889X

DOI: http://dx.doi.org/10.3389/fmolb.2021.650881

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


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.

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Last updated on 2021-24-06 at 08:28