The Interaction Mechanism of Intrinsically Disordered PP2A Inhibitor Proteins ARPP-16 and ARPP-19 With PP2A
Year of publication
2021
Authors
Thapa, Chandan; Roivas, Pekka; Haataja, Tatu; Permi, Perttu; Pentikäinen, Ulla
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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Publication type
Publication format
Article
Parent publication type
Journal
Article type
Original article
Audience
ScientificPeer-reviewed
Peer-ReviewedMINEDU's publication type classification code
A1 Journal article (refereed), original researchPublication channel information
Publisher
Volume
8
Article number
650881
ISSN
Publication forum
Publication forum level
1
Open access
Open access in the publisher’s service
Yes
Open access of publication channel
Fully open publication channel
Self-archived
Yes
Other information
Fields of science
Biochemistry, cell and molecular biology; Biomedicine
Keywords
[object Object],[object Object],[object Object],[object Object]
Publication country
Switzerland
Internationality of the publisher
International
International co-publication
No
Co-publication with a company
No
DOI
10.3389/fmolb.2021.650881
The publication is included in the Ministry of Education and Culture’s Publication data collection
Yes