The Ki-67 and RepoMan mitotic phosphatases assemble via an identical, yet novel mechanism

Kumar, Ganesan Senthil; Gokhan, Ezgi; Munter, Sofie De; Bollen, Mathieu; Vagnarelli, Paola; Peti, Wolfgang; Page, Rebecca

doi:10.7554/elife.16539

Cited by 61 publications

(85 citation statements)

References 44 publications

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“…2A). The interactions mediated by the 'V' and 'F' residues in the RVxF motif were also observed in a number of PP1 complex structures [27,[30][31][32][33][34][35][36][37]. There are a few noticeable differences between our structure and the previously reported structure.…”

Section: A Highly Conserved Region In G M Interacts With Pp1csupporting

confidence: 53%

Structural basis for protein phosphatase 1 recruitment by glycogen‐targeting subunits

Deng

Xiang

2018

The FEBS Journal

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The rate‐limiting enzymes in glycogen metabolism are subject to regulation by reversible phosphorylation. The glycogen‐targeted protein phosphatase 1 (PP1) holoenzyme catalyzes their dephosphorylation. It is composed of a catalytic subunit (PP1C) and a glycogen‐targeting subunit (G subunit). To date, seven G subunits have been identified. They all contain an RVxF PP1C‐binding motif. The interactions between this motif in the skeletal muscle‐specific GM and PP1C have been revealed by structural studies. However, whether elements outside of this motif contribute to the interaction with PP1C is not clear. In this study, we found that residues next to the RVxF motif in GM also mediate interactions to PP1C and revealed the mechanism of the interaction by structural studies. Sequence analysis revealed that the PP1C‐binding region in GM is highly conserved among G subunits. Consistently, we found that the equivalent region in the liver‐enriched GL adopts a similar structure upon binding PP1C. Dephosphorylation experiments indicated that this region and the glycogen‐binding region in GM cooperate to stimulate PP1C's activity toward glycogen‐associated substrates. Databases The structure factors and coordinates for the PP1Cα‐GM (1–99) and PP1Cα‐GL (31–105) complexes have been deposited into the Protein Data Bank (http://www.pdb.org), with the accession codes http://www.rcsb.org/pdb/search/structidSearch.do?structureId=5ZQV and http://www.rcsb.org/pdb/search/structidSearch.do?structureId=5ZT0, respectively.

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Section: A Highly Conserved Region In G M Interacts With Pp1csupporting

confidence: 53%

Structural basis for protein phosphatase 1 recruitment by glycogen‐targeting subunits

Deng

Xiang

2018

The FEBS Journal

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“…This therefore suggests that PP1 is necessary for heterochromatin formation. However, tethering PP1 to the locus per se (via the PP1-binding domain from Ki-67 (refs 23, 24)) is not sufficient to restore the level of recruitment achieved by the Repo-Man/PP1 complex (Fig. 3b).…”

Section: Resultsmentioning

confidence: 99%

Repo-Man/PP1 regulates heterochromatin formation in interphase

et al. 2017

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Repo-Man is a protein phosphatase 1 (PP1) targeting subunit that regulates mitotic progression and chromatin remodelling. After mitosis, Repo-Man/PP1 remains associated with chromatin but its function in interphase is not known. Here we show that Repo-Man, via Nup153, is enriched on condensed chromatin at the nuclear periphery and at the edge of the nucleopore basket. Repo-Man/PP1 regulates the formation of heterochromatin, dephosphorylates H3S28 and it is necessary and sufficient for heterochromatin protein 1 binding and H3K27me3 recruitment. Using a novel proteogenomic approach, we show that Repo-Man is enriched at subtelomeric regions together with H2AZ and H3.3 and that depletion of Repo-Man alters the peripheral localization of a subset of these regions and alleviates repression of some polycomb telomeric genes. This study shows a role for a mitotic phosphatase in the regulation of the epigenetic landscape and gene expression in interphase.

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“…The invariant SLiM residues place some constraints on the type of kinase inputs that are tolerated within the motifs themselves (supp. fig.7), but phosphorylation outside of these regions can also regulate phosphatase binding (Kumar et al, 2016;Qian et al, 2015). Furthermore, PP1 uses co-operative interaction with other SLiMs, and some of these, such as the SILK motif in Knl1, are also phospho-inhibitable (Liu et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…almost 700 unique proteins (supp.table.1). Motif analysis demonstrates that serines and threonines are statistically enriched at positions within each motif where phosphorylation is known to inhibit (RVxF) or enhance (LxxIxE) phosphatase interaction ( fig.6a,b) (Hertz et al, 2016;Kim et al, 2003;Kumar et al, 2016;Nasa et al, 2018;Wang et al, 2016a;Wang et al, 2016b). Furthermore, up to 25% of the validated motifs are known to be phosphorylated in vivo, and 50% of the RVxF and 100% of the LxxIxE motifs contain phosphorylatable residues at the key positions ( fig.6c-e); which is a statistically significant enrichment (see amino acid matrices in supp.table.1).…”

Section: Phospho-regulation Is a Common Feature Of Rvxf And Lxxixe Slimsmentioning

confidence: 99%

“…Furthermore, up to 25% of the validated motifs are known to be phosphorylated in vivo, and 50% of the RVxF and 100% of the LxxIxE motifs contain phosphorylatable residues at the key positions ( fig.6c-e); which is a statistically significant enrichment (see amino acid matrices in supp.table.1). It should be noted that phosphorylation of residues outside of the core RVxF region can also inhibit PP1 binding (Kumar et al, 2016;Qian et al, 2015). Furthermore, the negatively charged surface that surrounds the RVxF pocket on PP1 ( fig.6f), could potentially mediate many other electrostatic interactions that are inhibitable by phosphorylation.…”

Section: Phospho-regulation Is a Common Feature Of Rvxf And Lxxixe Slimsmentioning

confidence: 99%

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PP1 and PP2A use opposite phospho-dependencies to control distinct processes at the kinetochore

Smith

Cordeiro

Davey

et al. 2019

Preprint

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PP1 and PP2A-B56 are major serine/threonine phosphatase families that achieve specificity by colocalising with substrates. At the kinetochore, however, both phosphatases localise to an almost identical molecular space and yet they still manage to regulate unique pathways and processes. By switching or modulating the positions of PP1/PP2A-B56 at kinetochores, we show that their unique downstream effects are not due to either the identity of the phosphatase or its precise location. Instead, these phosphatases signal differently because their kinetochore recruitment can be either inhibited (PP1) or enhanced (PP2A) by phosphorylation inputs. Mathematical modelling explains how these inverse phospho-dependencies elicit unique forms of crossregulation and feedback, which allows otherwise indistinguishable phosphatases to produce distinct network behaviours and control different mitotic processes. Therefore, the kinetochore uses PP1 and PP2A-B56 because their binding motifs respond to kinase inputs in opposite ways. Genome-wide motif analysis suggests that many other pathways also select for these same key features, implying that these similar catalytic enzymes may have diverged during evolution to allow opposite modes of phospho-regulation.

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The Ki-67 and RepoMan mitotic phosphatases assemble via an identical, yet novel mechanism

Cited by 61 publications

References 44 publications

Structural basis for protein phosphatase 1 recruitment by glycogen‐targeting subunits

Structural basis for protein phosphatase 1 recruitment by glycogen‐targeting subunits

Repo-Man/PP1 regulates heterochromatin formation in interphase

PP1 and PP2A use opposite phospho-dependencies to control distinct processes at the kinetochore

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