Evolution and functional cross‐talk of protein post‐translational modifications

Beltrão, Pedro; Bork, Peer; Krogan, Nevan J.; Noort, Vera van

doi:10.1002/msb.201304521

Cited by 322 publications

(306 citation statements)

References 121 publications

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“…Interestingly, IDRs show other parallels with noncoding DNA (18,23,24). For example, nonconserved clusters of phosphorylation sites in IDRs are reminiscent of nonconserved transcription factor binding sites in enhancers.…”

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confidence: 99%

Selection maintains signaling function of a highly diverged intrinsically disordered region

Zarin

Tsai

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Intrinsically disordered regions (IDRs) are characterized by their lack of stable secondary or tertiary structure and comprise a large part of the eukaryotic proteome. Although these regions play a variety of signaling and regulatory roles, they appear to be rapidly evolving at the primary sequence level. To understand the functional implications of this rapid evolution, we focused on a highly diverged IDR in Saccharomyces cerevisiae that is involved in regulating multiple conserved MAPK pathways. We hypothesized that under stabilizing selection, the functional output of orthologous IDRs could be maintained, such that diverse genotypes could lead to similar function and fitness. Consistent with the stabilizing selection hypothesis, we find that diverged, orthologous IDRs can mostly recapitulate wildtype function and fitness in S. cerevisiae. We also find that the electrostatic charge of the IDR is correlated with signaling output and, using phylogenetic comparative methods, find evidence for selection maintaining this quantitative molecular trait despite underlying genotypic divergence.C urrent predictions suggest that close to 40% of all proteins in eukaryotic organisms are either entirely disordered or contain sizeable regions that are disordered, meaning they do not autonomously fold into defined secondary or tertiary structures (1, 2). These intrinsically disordered regions (IDRs) are thought to have important implications for protein function (3, 4) and are known to play regulatory roles, often through short linear motifs (SLiMs) that control protein-protein interactions, localization, degradation, and posttranslational modifications (5, 6). Although proteome-wide studies have provided in silico evidence for conservation of length (7) and composition (8) in some IDRs, reports of increased rates of insertions and deletions (9-13) and amino acid substitutions (14) in IDRs are indicative of their rapid evolution compared with ordered regions. In addition, although some SLiMs are indeed conserved in IDRs (15-17), others appear in clusters where precise position and number are not conserved (18)(19)(20). Although it is reasonable to assume that conservation of sequence in IDRs is indicative of functional conservation of SLiMs, it is more difficult to interpret the functional consequences of IDRs that are highly diverged at the sequence level: These may represent either nonfunctional sequences evolving in the absence of constraint or weakly constrained functional elements that are gained or lost in a compensatory manner [undergoing evolutionary turnover (as described in refs. 18, 21)], such that they are not conserved at the amino acid sequence level.Like IDRs, noncoding DNA often shows relatively rapid evolution and weak constraints at the sequence level (22). Interestingly, IDRs show other parallels with noncoding DNA (18,23,24). For example, nonconserved clusters of phosphorylation sites in IDRs are reminiscent of nonconserved transcription factor binding sites in enhancers. Although these enhancers and the bi...

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confidence: 99%

Selection maintains signaling function of a highly diverged intrinsically disordered region

Zarin

Tsai

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The basic proteome of an organism is greatly expanded and diversified through post-translational modifications (Beltrao et al 2013). Covalent attachment of small molecules such as phosphate groups or small proteins such as ubiquitin alters the functional properties of target proteins in various ways.…”

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confidence: 99%

Loss of the SUMO protease Ulp2 triggers a specific multichromosome aneuploidy

et al. 2016

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Post-translational protein modification by the small ubiquitin-related modifier (SUMO) regulates numerous cellular pathways, including transcription, cell division, and genome maintenance. The SUMO protease Ulp2 modulates many of these SUMO-dependent processes in budding yeast. From whole-genome RNA sequencing (RNA-seq), we unexpectedly discovered that cells lacking Ulp2 display a twofold increase in transcript levels across two particular chromosomes: chromosome I (ChrI) and ChrXII. This is due to the two chromosomes being present at twice their normal copy number. An abnormal number of chromosomes, termed aneuploidy, is usually deleterious. However, development of specific aneuploidies allows rapid adaptation to cellular stresses, and aneuploidy characterizes most human tumors. Extra copies of ChrI and ChrXII appear quickly following loss of active Ulp2 and can be eliminated following reintroduction of ULP2, suggesting that aneuploidy is a reversible adaptive mechanism to counteract loss of the SUMO protease. Importantly, increased dosage of two genes on ChrI-CLN3 and CCR4, encoding a G 1 -phase cyclin and a subunit of the Ccr4-Not deadenylase complex, respectively-suppresses ulp2Δ aneuploidy, suggesting that increased levels of these genes underlie the aneuploidy induced by Ulp2 loss. Our results reveal a complex aneuploidy mechanism that adapts cells to loss of the SUMO protease Ulp2.

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“…With the development of mass spectrometry (MS) techniques, increasing number of PTM sites have been identified (7,8). Multiple PTMs within one protein can coordinately determine a functional outcome, which is called PTM crosstalk (9). For example, the Set9-mediated methylation of Lys 372 on p53 inhibits the Smyd2-mediated methylation of Lys 370, and consequently represses the p53 activity (10).…”

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Systematic Characterization and Prediction of Post-Translational Modification Cross-Talk *

Huang

Xu²,

Zhou

et al. 2015

Molecular & Cellular Proteomics

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Post-translational modification (PTM) 1 plays an important role in regulating the functions of proteins. PTMs of multiple residues on one protein may work together to determine a functional outcome, which is known as PTM crosstalk. Identification of PTM cross-talks is an emerging theme in proteomics and has elicited great interest, but their properties remain to be systematically characterized. To this end, we collected 193 PTM cross-talk pairs in 77 human proteins from the literature and then tested location preference and co-evolution at the residue and modification levels. We found that cross-talk events preferentially occurred among nearby PTM sites, especially in disordered protein regions, and cross-talk pairs tended to co-evolve. Given the properties of PTM cross-talk pairs, a naïve Bayes classifier integrating different features was built to predict cross-talks for pairwise combination of PTM sites. By using a 10-fold cross-validation, the integrated prediction model showed an area under the receiver operating characteristic (ROC) curve of 0.833, superior to using any individual feature alone. The prediction performance was also demonstrated to be robust to the biases in the collected PTM cross-talk pairs. The integrated approach has the potential for large-scale prioritization of PTM cross-talk candidates for functional validation and was implemented as a web server available at

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Evolution and functional cross‐talk of protein post‐translational modifications

Cited by 322 publications

References 121 publications

Selection maintains signaling function of a highly diverged intrinsically disordered region

Selection maintains signaling function of a highly diverged intrinsically disordered region

Loss of the SUMO protease Ulp2 triggers a specific multichromosome aneuploidy

Systematic Characterization and Prediction of Post-Translational Modification Cross-Talk *

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