Abstract
Although kinase mutations have been identified in various human diseases, much less is known about protein phosphatases. Here, we show that all apoptosis-stimulating proteins of p53 (ASPP) family members can bind protein phosphatase 1 (PP1) via two distinct interacting motifs. ASPP2 interacts with PP1 through an RVXF PP1 binding motif, whereas the inhibitory member of the ASPP family (iASPP) interacts with PP1 via a noncanonical motif (RNYF) that is located within its Src homology 3 domain (SH3). Phe-815 is crucial in mediating iASPP/PP1 interaction, and iASPP(F815A) fails to inhibit the transcriptional and apoptotic function of p53. This study identifies iASPP as a new binding partner of PP1, interacting through a noncanonical PP1 binding motif.
Highlights
Regulatory subunits confer substrate specificity to protein phosphatases
We have shown that the three members of the apoptosis-stimulating proteins of p53 (ASPP) family, ASPP1, ASPP2, and inhibitory member of the ASPP family (iASPP), can bind the catalytic subunit of phosphatase 1 (PP1) in cells
ASPP1 and ASPP2 both contain a conserved classical RVXF PP1 binding motif, and our data have confirmed that this domain is required for full-length ASPP2 to interact with PP1 because, when it was mutated, ASPP2 and PP1 could no longer interact
Summary
Results: iASPP, unlike ASPP2, interacts with protein phosphatase 1 (PP1) via a noncanonical binding motif within its SH3 domain. The substrate selectivity of PP1 is largely conferred by its specific regulatory subunits, which are extremely varied Their association with PP1 catalytic subunits may result in Ͼ100 different PP1 enzymes, providing the needed diversity to counterbalance the Ser/Thr kinases. An RVXF-containing ASPP2 fragment was able to modulate the activity of PP1 by eliminating its effect on glycogen phosphorylase, but not on myosin-P light chains [7] Together, these results suggest that ASPP2 may be a regulatory subunit for PP1 in vitro. They exhibit a high degree of homology in their C termini, which contain their signature sequences of ankyrin repeats, an SH3 domain, and a proline-rich region They have mainly been studied in the context of their ability to interact with, and to regulate, the apoptotic function of p53 and its fam-. Detailed analysis revealed that iASPP contains a novel PP1 binding motif within its SH3 domain and that Phe-815 of iASPP is critical in mediating the iASPP/PP1 interaction and important for iASPP inhibition of p53 function
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