In‐depth and 3‐dimensional exploration of the budding yeast phosphoproteome

Lanz, Michael; Yugandhar, Kumar; Gupta, Shagun; Sanford, Ethan J.; Faça, Vitor M.; Vega, Stephanie; Joiner, Aaron M.N.; Fromme, J. Christopher; Yu, Haiyuan; Smolka, Marcus B.

doi:10.15252/embr.202051121

Cited by 112 publications

(98 citation statements)

References 84 publications

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“…The PIP-Stop Score (PSS) was defined as a new parameter to estimate the likelihood that a given PX domain contains a PIP-stop that governs its binding to membranes. Post-translational modifications (PTMs) were obtained from cBioportal [ 14 ], dbPTM [ 98 ], PhosphoSite [ 15 ], qPTM [ 99 ] and an augmented human phosphoproteomic database [ 100 ], while yeast data were obtained from PhosphoGrid [ 101 ] and SuperPhos [ 102 ], Drosophila melanogaster data from iProteinDB [ 103 ] and Danio rerio and Caenorhabditis elegans data from PTMcode2 [ 104 ], providing multiple proteome-wide coverages, with our manual curation excluding duplicates. As a standardized measure that integrates data from multiple cell types, PSS balances out the effects of differential protein expression in various tissues, which can bias observed modification levels.…”

Section: Methodsmentioning

confidence: 99%

Regulation of the Phosphoinositide Code by Phosphorylation of Membrane Readers

Kervin

Overduin

2021

Cells

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The genetic code that dictates how nucleic acids are translated into proteins is well known, however, the code through which proteins recognize membranes remains mysterious. In eukaryotes, this code is mediated by hundreds of membrane readers that recognize unique phosphatidylinositol phosphates (PIPs), which demark organelles to initiate localized trafficking and signaling events. The only superfamily which specifically detects all seven PIPs are the Phox homology (PX) domains. Here, we reveal that throughout evolution, these readers are universally regulated by the phosphorylation of their PIP binding surfaces based on our analysis of existing and modelled protein structures and phosphoproteomic databases. These PIP-stops control the selective targeting of proteins to organelles and are shown to be key determinants of high-fidelity PIP recognition. The protein kinases responsible include prominent cancer targets, underscoring the critical role of regulated membrane readership.

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Section: Methodsmentioning

confidence: 99%

Regulation of the Phosphoinositide Code by Phosphorylation of Membrane Readers

Kervin

Overduin

2021

Cells

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“…Several phospho-proteomic studies have identified at least 75 new phospho-sites in 10 of the 12 subunits of S. cerevisiae RNAPII (Supplementary Table S1), 55 of them distributed along specific RNAPII subunits (Rpb1, Rpb2, Rpb3 Rpb4, and Rpb9) and 20 in shared subunits with RNAPI and RNAPIII (Rpb5, Rpb6, Rpb8, Rpb10, and Rpb12) (Albuquerque et al, 2008;Pultz et al, 2012;Swaney et al, 2013;Sostaric et al, 2018;MacGilvray et al, 2020;Lanz et al, 2021;Richard et al, 2021). However, it is unknown whether all these residues are phosphorylated in vivo and if they form part of a regulatory mechanism to control the biogenesis of RNAPII transcripts.…”

Section: Rnapii Phosphorylationmentioning

confidence: 99%

“…The subunits shared by the three RNAPs (Rpb5, Rpb6, Rpb8, Rpb10, and Rpb12) are also phospho-proteins (Supplementary Table S1) (Albuquerque et al, 2008;Swaney et al, 2013;Sostaric et al, 2018;MacGilvray et al, 2020;Lanz et al, 2021). For instance, Rpb5 and Rpb6 contain phospho-sites (S158, and Y88 and T82, respectively) localized in regions important for Rpb5 and Rpb6 assembly to RNAPII (Cramer et al, 2001;Tan et al, 2003;Zaros et al, 2007).…”

Section: Rnapii Phosphorylationmentioning

confidence: 99%

“…Only one residue, Rpa190-S685, was suggested to play a role in rRNA cleavage/elongation or termination (Gerber et al, 2008). To date, 115 site-specific phosphorylations have been identified, mostly in phospho-proteomic studies, distributed along all the 14 RNAPI subunits (Ficarro et al, 2002;Albuquerque et al, 2008;Holt et al, 2009;Soulard et al, 2010;Pultz et al, 2012;Swaney et al, 2013;Sostaric et al, 2018;MacGilvray et al, 2020;Lanz et al, 2021). We have compiled all these sites in Supplementary Table S1.…”

Section: Rnapi Phosphorylationmentioning

confidence: 99%

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Regulation of Eukaryotic RNAPs Activities by Phosphorylation

González-Jiménez

Campos

Navarro

et al. 2021

Front. Mol. Biosci.

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Evolutionarily conserved kinases and phosphatases regulate RNA polymerase II (RNAPII) transcript synthesis by modifying the phosphorylation status of the carboxyl-terminal domain (CTD) of Rpb1, the largest subunit of RNAPII. Proper levels of Rpb1-CTD phosphorylation are required for RNA co-transcriptional processing and to coordinate transcription with other nuclear processes, such as chromatin remodeling and histone modification. Whether other RNAPII subunits are phosphorylated and influences their role in gene expression is still an unanswered question. Much less is known about RNAPI and RNAPIII phosphorylation, whose subunits do not contain functional CTDs. However, diverse studies have reported that several RNAPI and RNAPIII subunits are susceptible to phosphorylation. Some of these phosphorylation sites are distributed within subunits common to all three RNAPs whereas others are only shared between RNAPI and RNAPIII. This suggests that the activities of all RNAPs might be finely modulated by phosphorylation events and raises the idea of a tight coordination between the three RNAPs. Supporting this view, the transcription by all RNAPs is regulated by signaling pathways that sense different environmental cues to adapt a global RNA transcriptional response. This review focuses on how the phosphorylation of RNAPs might regulate their function and we comment on the regulation by phosphorylation of some key transcription factors in the case of RNAPI and RNAPIII. Finally, we discuss the existence of possible common mechanisms that could coordinate their activities.

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“…The TSRD extends from amino acid 399 to 1021 and is enriched for serines and threonines, but not enriched for cysteines. This region has 23 / 24 of the detected phosphorylation sites in Ira2 (Holt et al, 2009;Lanz et al, 2021;Swaney et al, 2013). We chose the start of the TSRD at a cluster of serines and the end at the last detected phosphorylated residue.…”

Section: Designation Of Ira2 Domainsmentioning

confidence: 99%

Multiple causal DNA variants in a single gene affect gene expression intrans

Lutz

Dyke

Albert

2021

Preprint

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Identifying the specific causal DNA differences in a genome that contribute to variation in phenotypic traits is a key goal of genetic research. Trans-acting DNA variants that alter gene expression are important sources of genetic variation. Several genes are known to carry single causal variants that affect the expression of numerous genes in trans. Whether these single variants are representative of the architecture of trans-acting variation is unknown. Here, we studied the gene IRA2, which carries variants with broad, trans-acting effects on gene expression in two strains of the yeast Saccharomyces cerevisiae. We found that IRA2 contains at least seven causal nonsynonymous variants. The causal variants were located throughout the gene body and included a pair of neighboring variants with opposing effects that largely canceled each other out. The causal variants showed evidence for non-additive epistatic interactions, in particular among variants at the 5' end of the gene. These results show that the molecular basis of trans-acting variation can involve considerable complexity even within a single gene.

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In‐depth and 3‐dimensional exploration of the budding yeast phosphoproteome

Cited by 112 publications

References 84 publications

Regulation of the Phosphoinositide Code by Phosphorylation of Membrane Readers

Regulation of the Phosphoinositide Code by Phosphorylation of Membrane Readers

Regulation of Eukaryotic RNAPs Activities by Phosphorylation

Multiple causal DNA variants in a single gene affect gene expression intrans

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