The Interaction Mechanism of Intrinsically Disordered PP2A Inhibitor Proteins ARPP-16 and ARPP-19 With PP2A
Publiceringsår
2021
Upphovspersoner
Thapa, Chandan; Roivas, Pekka; Haataja, Tatu; Permi, Perttu; Pentikäinen, Ulla
Abstrakt
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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Publikationstyp
Publikationsform
Artikel
Moderpublikationens typ
Tidning
Artikelstyp
En originalartikel
Målgrupp
VetenskapligKollegialt utvärderad
Kollegialt utvärderadUKM:s publikationstyp
A1 Originalartikel i en vetenskaplig tidskriftPublikationskanalens uppgifter
Förläggare
Volym
8
Artikelnummer
650881
ISSN
Publikationsforum
Publikationsforumsnivå
1
Öppen tillgång
Öppen tillgänglighet i förläggarens tjänst
Ja
Öppen tillgång till publikationskanalen
Helt öppen publikationskanal
Parallellsparad
Ja
Övriga uppgifter
Vetenskapsområden
Biokemi, cell- och molekylärbiologi; Biomedicinska vetenskaper
Nyckelord
[object Object],[object Object],[object Object],[object Object]
Publiceringsland
Schweiz
Förlagets internationalitet
Internationell
Internationell sampublikation
Nej
Sampublikation med ett företag
Nej
DOI
10.3389/fmolb.2021.650881
Publikationen ingår i undervisnings- och kulturministeriets datainsamling
Ja