Expanding the PP2A Interactome by Defining a B56-Specific SLiM
Open accessAbstract
Specific interactions between proteins govern essential physiological processes including signaling. Many enzymes, especially the family of serine/threonine phosphatases (PSPs: PP1, PP2A, and PP2B/calcineurin/CN), recruit substrates and regulatory proteins by binding short linear motifs (SLiMs), short sequences found within intrinsically disordered regions that mediate specific protein-protein interactions. While tremendous progress had been made in identifying where and how SLiMs bind PSPs, especially PP1 and CN, essentially nothing is known about how SLiMs bind PP2A, a validated cancer drug target. Here we describe three structures of a PP2A-SLiM interaction (B56:pS-RepoMan, B56:pS-BubR1, and B56:pSpS-BubR1), show that this PP2A-specific SLiM is defined as LSPIxE, and then use these data to discover scores of likely PP2A regulators and substrates. Together, these data provide a powerful approach not only for dissecting PP2A interaction networks in cells but also for targeting PP2A diseases, such as cancer.
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B56 proteins recognize target proteins via a conserved binding pocket that binds LxxIxE consensus motifs.
“The B56 proteins recognize their target proteins via a conserved binding pocket that binds to short linear motifs (SLIMs) with a LxxIxE consensus sequence in the target protein10,14–16.”
From Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A (2023) · cites this paper as [14]
The large overlap of identified peptides between different B′-family members is consistent with the high sequence identity of their structural cores, where identical residues of B′ regulatory subunits are involved in motif binding.
“The large overlap of the identified peptides between different B′-family members is consistent with the high sequence identity of their structural cores, where identical residues of B′ regulatory subunits are involved in motif binding [12, 20, 21].”
From PP2A-B′ holoenzyme substrate recognition, regulation and role in cytokinesis (2017) · cites this paper as [21]
Previous studies showed that phosphorylation or negatively charged residues at positions 2, 7, 8 and 9 enhance B′ binding.
“Previous studies showed that phosphorylation or negatively charged residues at positions 2, 7, 8 and 9 enhance B′ binding [12, 17, 21].”
From PP2A-B′ holoenzyme substrate recognition, regulation and role in cytokinesis (2017) · cites this paper as [21]
Our study corroborates the previous results that phosphorylation or negatively charged residues at positions 2, 7, 8 and 9 enhance B′ binding.
“Our study also corroborates the previous results that phosphorylation or negatively charged residues at positions 2, 7, 8 and 9 enhance B′ binding [12, 17, 21].”
From PP2A-B′ holoenzyme substrate recognition, regulation and role in cytokinesis (2017) · cites this paper as [21]
Short linear motifs such as LxxIxE and LSPIxE have been identified and play a pivotal role in substrate targeting and specific protein-protein interactions.
“Furthermore, several studies have reported the identification of short linear motifs (SLiMs), such as LxxIxE [ 61 ] and LSPIxE [ 62 ]. These motifs play a pivotal role in substrate targeting and facilitating specific protein–protein interactions.”
From Targeting PP2A in cancer: an underrated option (2025) · cites this paper as [62]
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- Authors
- Wang, X., Bajaj, R., Bollen, M., Peti, W., & Page, R.
- Affiliations
- Brown University (US)
- KU Leuven (BE)
- Corresponding author
- Page, Rebecca
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 24
- Issue
- 12
- Pages
- 2174-2181
- ISSN
- 0969-2126 (ISSN-L)
- PMC
- PMC5180209
- OpenAlex
- W2539509011
- Cited by
- 149
- References
- 30
- Citations by year
- 2026: 10 · 2025: 21 · 2024: 9 · 2023: 17 · 2022: 17 · 2021: 26 · 2020: 21 · 2019: 15 · 2018: 9 · 2017: 4
- FWCI
- 4.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 370 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Structure (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Lirias (submittedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- NINDS (R01NS091336)
- NIGMS (R01GM098482)
- Fund for Scientific Research-Flanders (G.0473.12, G.0482.12)
- Flemish Concerted Research Action (GOA 15/016)
- US DOE, Office of Science, Office of Basic Energy Sciences (DE-AC02-76SF00515)
- DOE Office of Biological and Environmental Research
- NIH-NIGMS (P41GM103393)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- protein phosphatase 2A, short linear motifs, protein-protein interaction, serine/threonine phosphatase, intrinsically disordered regions, BubR1, phosphoserine, protein complex structure, cancer drug targets
- MeSH terms
- Binding Sites, Carrier Proteins, Humans, Models, Molecular, Nuclear Proteins, Phosphorylation, Protein Binding, Serine, Protein Serine-Threonine Kinases, Crystallography, X-Ray, Cell Cycle Proteins, Amino Acid Motifs, Protein Phosphatase 2
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