A dynamic charge-charge interaction modulates PP2A:B56 substrate recruitment

Wang, Xinru; Garvanska, Dimitriya H; Nasa, Isha; Ueki, Yumi; Zhang, Gang; Kettenbach, Arminja N.; Peti, Wolfgang; Nilsson, Jakob; Page, Rebecca

doi:10.7554/elife.55966

Cited by 41 publications

(51 citation statements)

References 59 publications

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“…This R2 region includes a higher density of positively charged residues that enhance binding most likely via charged:charged interactions. Indeed, this has also been recently shown for protein phosphatase 2B (PP2B; PP3; Calcineurin) and the B56 regulatory subunit of PP2A, where these dynamic charged:charged interactions were shown to play a role in substrate specificity (Hendus-Altenburger et al, 2019;Wang et al, 2020). Thus, such interactions, which have been recently recognized to be critical for the interaction of IDPs with their target proteins and allow for increased entropy, are likely important for substrate recruitment and specificity by different phosphatases.…”

Section: Discussionmentioning

confidence: 74%

PP2A/B55α substrate recruitment as defined by the retinoblastoma-related protein p107

Fowle

Zhao

et al. 2021

Preprint

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Protein phosphorylation is a reversible post-translation modification essential in cell signaling. This study addresses a long-standing question as to how the most abundant serine/threonine Protein-Phosphatase 2 (PP2A) holoenzyme, PP2A/B55α, specifically recognizes substrates and presents them to the enzyme active site. Here, we show how the PP2A regulatory subunit B55α recruits p107, a pRB-related tumor suppressor and B55α substrate. Using molecular and cellular approaches, we identified a conserved region 1(615-626) encompassing the strongest p107 binding site. This enabled us to identify an "HxRVxxV619-625" short linear motif (SLiM) in p107 as necessary for B55α binding and dephosphorylation of pSer-615 in vitro and in cells. Numerous B55α/PP2A substrates, including TAU, contain a related SLiM C-terminal from a proximal phosphosite, "p[ST]-P-x(5-10)-[RK]-V-x-x-[VI]-R". Mutation of conserved SLiM residues in TAU dramatically inhibits PP2A/B55α-mediated dephosphorylation, validating its generality. A data-guided computational model details the residue interactions from the conserved p107 SLiM, the B55α groove, and phosphosite presentation.

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Section: Discussionmentioning

confidence: 74%

PP2A/B55α substrate recruitment as defined by the retinoblastoma-related protein p107

Fowle

Zhao

et al. 2021

Preprint

Self Cite

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“…1D). As an example, Kif4A T799 and ADAM17 T735 are known targets of PP2A-B56 and these two proteins contain validated LxxIxE motifs (Bastos et al, 2014;Kruse et al, 2020;Wang et al, 2020). Furthermore, RacGAP1 S203, BubR1 T508 and ESPL1 S1475 are close to validated LxxIxE motifs supporting the strength of the screening approach.…”

Section: A Screen For Pp2a-b56 Mitotic Substrates Identifies Cdc20mentioning

confidence: 72%

Coupling of Cdc20 inhibition and activation by BubR1

Hein

Garvanska

Nasa

et al. 2020

Preprint

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Tight regulation of the APC/C-Cdc20 ubiquitin ligase that targets Cyclin B1 for degradation is important for mitotic fidelity. The spindle assembly checkpoint (SAC) inhibits Cdc20 through the mitotic checkpoint complex (MCC). In addition, phosphorylation of Cdc20 by Cyclin B1-Cdk1 independently inhibits APC/C-Cdc20 activation. This creates a conundrum for how Cdc20 gets activated prior to Cyclin B1 degradation. Here we show that the MCC component BubR1 harbours both Cdc20 inhibition and activation activities, allowing for cross-talk between the two Cdc20 inhibition pathways. Specifically BubR1 acts as a substrate specifier for PP2A-B56 to enable efficient Cdc20 dephosphorylation in the MCC. A mutant Cdc20 mimicking the dephosphorylated state escapes a mitotic checkpoint arrest arguing that restricting Cdc20 dephosphorylation to the MCC is important. Collectively our work reveals how Cdc20 can be dephosphorylated in the presence of Cyclin B1-Cdk1 activity without causing premature anaphase onset.

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“…It was recently shown that a subset of PP2A-B56 interactors harbour a positively charged motif, complementary to an acidic patch on B56 34 . Deltaretroviral INs do not engage with this acidic patch but appear to have evolved to use an interface employed by other PP2A-B56 interactors, like BUBR1 and CHK2 (Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Cryo-EM structure of the deltaretroviral intasome in complex with the PP2A regulatory subunit B56γ

et al. 2020

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Human T-cell lymphotropic virus type 1 (HTLV-1) is a deltaretrovirus and the most oncogenic pathogen. Many of the ~20 million HTLV-1 infected people will develop severe leukaemia or an ALS-like motor disease, unless a therapy becomes available. A key step in the establishment of infection is the integration of viral genetic material into the host genome, catalysed by the retroviral integrase (IN) enzyme. Here, we use X-ray crystallography and single-particle cryo-electron microscopy to determine the structure of the functional deltaretroviral IN assembled on viral DNA ends and bound to the B56γ subunit of its human host factor, protein phosphatase 2 A. The structure reveals a tetrameric IN assembly bound to two molecules of the phosphatase via a conserved short linear motif. Insight into the deltaretroviral intasome and its interaction with the host will be crucial for understanding the pattern of integration events in infected individuals and therefore bears important clinical implications.

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A dynamic charge-charge interaction modulates PP2A:B56 substrate recruitment

Cited by 41 publications

References 59 publications

PP2A/B55α substrate recruitment as defined by the retinoblastoma-related protein p107

PP2A/B55α substrate recruitment as defined by the retinoblastoma-related protein p107

Coupling of Cdc20 inhibition and activation by BubR1

Cryo-EM structure of the deltaretroviral intasome in complex with the PP2A regulatory subunit B56γ

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