Crystal structure of a PP2A B56-BubR1 complex and its implications for PP2A substrate recruitment and localization
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Protein phosphatase 2A (PP2A) accounts for the majority of total Ser/Thr phosphatase activities in most cell types and regulates many biological processes. PP2A holoenzymes contain a scaffold A subunit, a catalytic C subunit, and one of the regulatory/targeting B subunits. How the B subunit controls PP2A localization and substrate specificity, which is a crucial aspect of PP2A regulation, remains poorly understood. The kinetochore is a critical site for PP2A functioning, where PP2A orchestrates chromosome segregation through its interactions with BubR1. The PP2A-BubR1 interaction plays important roles in both spindle checkpoint silencing and stable microtubule-kinetochore attachment. Here we present the crystal structure of a PP2A B56-BubR1 complex, which demonstrates that a conserved BubR1 LxxIxE motif binds to the concave side of the B56 pseudo-HEAT repeats. The BubR1 motif binds to a groove formed between B56 HEAT repeats 3 and 4, which is quite distant from the B56 binding surface for PP2A catalytic C subunit and thus is unlikely to affect PP2A activity. In addition, the BubR1 binding site on B56 is far from the B56 binding site of shugoshin, another kinetochore PP2A-binding protein, and thus BubR1 and shugoshin can potentially interact with PP2A-B56 simultaneously. Our structural and biochemical analysis indicates that other proteins with the LxxIxE motif may also bind to the same PP2A B56 surface. Thus, our structure of the PP2A B56-BubR1 complex provides important insights into how the B56 subunit directs the recruitment of PP2A to specific targets.
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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 [15]
The Results section on the B56–BubR1 interface reports that BubR1’s LxxIxE motif binds B56 pockets and that the interacting B56 residues are conserved across human isoforms. The Discussion proposes this motif as a possible common recruitment signal, but does not establish that B56 proteins recognize their target proteins generally by this mechanism. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe 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 [20]
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- Authors
- Wang, J., Wang, Z., Yu, T., Yang, H., Virshup, D. M., Kops, G. J. P. L., Lee, S. H., Zhou, W., Li, X., Xu, W., & Rao, Z.
- Affiliations
- Nankai University (CN)
- University of Washington (US)
- Duke Medical Center (US)
- University Medical Center Utrecht (NL)
- Duke-NUS Medical School (SG)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Xu, Wenqing
- Rao, Zihe
- ORCID
- Venue
- Protein & Cell
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-06-28
- Volume
- 7
- Issue
- 7
- Pages
- 516-526
- ISSN
- 1674-800X (ISSN-L)
- 1674-8018
- PMC
- PMC4930772
- OpenAlex
- W2465181069
- Cited by
- 80
- References
- 43
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 7 · 2023: 7 · 2022: 5 · 2021: 11 · 2020: 12 · 2019: 10 · 2018: 4 · 2017: 9 · 2016: 2
- FWCI
- 5.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Protein & Cell (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion, other-oa)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion, other-oa)
- National University of Singapore (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Chinese Academy of Sciences (XDB08010303, XDB08020200)
- Nankai University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- protein phosphatase 2A, BubR1, kinetochore, spindle assembly checkpoint, shugoshin, substrate recruitment, protein localization, crystal structure
- MeSH terms
- Binding Sites, Humans, Multienzyme Complexes, Protein Serine-Threonine Kinases, Crystallography, X-Ray, Cell Cycle Proteins, Amino Acid Motifs, Protein Structure, Quaternary, Protein Phosphatase 2
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