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1.  The eukaryotic linear motif resource ELM: 10 years and counting 
Nucleic Acids Research  2013;42(D1):D259-D266.
The eukaryotic linear motif (ELM http://elm.eu.org) resource is a hub for collecting, classifying and curating information about short linear motifs (SLiMs). For >10 years, this resource has provided the scientific community with a freely accessible guide to the biology and function of linear motifs. The current version of ELM contains ∼200 different motif classes with over 2400 experimentally validated instances manually curated from >2000 scientific publications. Furthermore, detailed information about motif-mediated interactions has been annotated and made available in standard exchange formats. Where appropriate, links are provided to resources such as switches.elm.eu.org and KEGG pathways.
doi:10.1093/nar/gkt1047
PMCID: PMC3964949  PMID: 24214962
2.  Deciphering a global network of functionally associated post-translational modifications 
This study is the first large-scale comparative analysis of multiple types of post-translational modifications in different eukaryotic species. The resulting network of co-evolving and functionally associated modifications reveals the global landscape of post-translational regulation.
In all, 115 149 non-redundant post-translational modifications (PTMs) of 13 different types were collected from 8 eukaryotes.Comparison of evolution speed reveals that carboxylation is the most conserved while SUMOylation is the fastest evolving PTM type.Co-evolution of PTM pairs that co-occur within proteins reveals a vastly interconnected global network of functionally associated PTM types in eukaryotes.Central to the network of functionally associated PTM types appear phosphorylation, acetylation, ubiquitination and O-linked glycosylation that control both temporal events and processes that govern protein localization.
Various post-translational modifications (PTMs) fine-tune the functions of almost all eukaryotic proteins, and co-regulation of different types of PTMs has been shown within and between a number of proteins. Aiming at a more global view of the interplay between PTM types, we collected modifications for 13 frequent PTM types in 8 eukaryotes, compared their speed of evolution and developed a method for measuring PTM co-evolution within proteins based on the co-occurrence of sites across eukaryotes. As many sites are still to be discovered, this is a considerable underestimate, yet, assuming that most co-evolving PTMs are functionally associated, we found that PTM types are vastly interconnected, forming a global network that comprise in human alone >50 000 residues in about 6000 proteins. We predict substantial PTM type interplay in secreted and membrane-associated proteins and in the context of particular protein domains and short-linear motifs. The global network of co-evolving PTM types implies a complex and intertwined post-translational regulation landscape that is likely to regulate multiple functional states of many if not all eukaryotic proteins.
doi:10.1038/msb.2012.31
PMCID: PMC3421446  PMID: 22806145
post-translational modifications; protein regulation; proteomics; PTM code; PTM crosstalk
3.  Progressive postnatal motoneuron loss in mice lacking GDF-15 
The Journal of Neuroscience  2009;29(43):13640-13648.
GDF-15 is a widely expressed distant member of the TGF-ß superfamily with prominent neurotrophic effects on midbrain dopaminergic neurons. We show here that GDF-15 deficient mice exhibit progressive postnatal losses of spinal, facial, and trigeminal motoneurons. This deficit reaches a ~20% maximum at 6 months and is accompanied by losses of motor axons and significant impairment of rotarod skills. Similarly, sensory neurons in dorsal root ganglia (L4, L5) are reduced by 20%, while sympathetic neurons are not affected. GDF-15 is expressed and secreted by Schwann cells, retrogradely transported along adult sciatic nerve axons, and promotes survival of axotomized facial neurons as well as cultured motor, sensory, and sympathetic neurons. Despite striking similarities in the GDF-15 and CNTF knockout phenotypes, expression levels of CNTF and other neurotrophic factors in the sciatic nerve were unaltered suggesting that GDF-15 is a genuine novel trophic factor for motor and sensory neurons.
doi:10.1523/JNEUROSCI.1133-09.2009
PMCID: PMC3320210  PMID: 19864576
GDF-15; knockout; TGF-beta; motoneurons; dorsal root ganglia; Schwann cells; axon
4.  ELM—the database of eukaryotic linear motifs 
Nucleic Acids Research  2011;40(D1):D242-D251.
Linear motifs are short, evolutionarily plastic components of regulatory proteins and provide low-affinity interaction interfaces. These compact modules play central roles in mediating every aspect of the regulatory functionality of the cell. They are particularly prominent in mediating cell signaling, controlling protein turnover and directing protein localization. Given their importance, our understanding of motifs is surprisingly limited, largely as a result of the difficulty of discovery, both experimentally and computationally. The Eukaryotic Linear Motif (ELM) resource at http://elm.eu.org provides the biological community with a comprehensive database of known experimentally validated motifs, and an exploratory tool to discover putative linear motifs in user-submitted protein sequences. The current update of the ELM database comprises 1800 annotated motif instances representing 170 distinct functional classes, including approximately 500 novel instances and 24 novel classes. Several older motif class entries have been also revisited, improving annotation and adding novel instances. Furthermore, addition of full-text search capabilities, an enhanced interface and simplified batch download has improved the overall accessibility of the ELM data. The motif discovery portion of the ELM resource has added conservation, and structural attributes have been incorporated to aid users to discriminate biologically relevant motifs from stochastically occurring non-functional instances.
doi:10.1093/nar/gkr1064
PMCID: PMC3245074  PMID: 22110040
5.  Phospho.ELM: a database of phosphorylation sites—update 2011 
Nucleic Acids Research  2010;39(Database issue):D261-D267.
The Phospho.ELM resource (http://phospho.elm.eu.org) is a relational database designed to store in vivo and in vitro phosphorylation data extracted from the scientific literature and phosphoproteomic analyses. The resource has been actively developed for more than 7 years and currently comprises 42 574 serine, threonine and tyrosine non-redundant phosphorylation sites. Several new features have been implemented, such as structural disorder/order and accessibility information and a conservation score. Additionally, the conservation of the phosphosites can now be visualized directly on the multiple sequence alignment used for the score calculation. Finally, special emphasis has been put on linking to external resources such as interaction networks and other databases.
doi:10.1093/nar/gkq1104
PMCID: PMC3013696  PMID: 21062810
6.  Phospho3D 2.0: an enhanced database of three-dimensional structures of phosphorylation sites 
Nucleic Acids Research  2010;39(Database issue):D268-D271.
Phospho3D is a database of three-dimensional (3D) structures of phosphorylation sites (P-sites) derived from the Phospho.ELM database, which also collects information on the residues surrounding the P-site in space (3D zones). The database also provides the results of a large-scale structural comparison of the 3D zones versus a representative dataset of structures, thus associating to each P-site a number of structurally similar sites. The new version of Phospho3D presents an 11-fold increase in the number of 3D sites and incorporates several additional features, including new structural descriptors, the possibility of selecting non-redundant sets of 3D structures and the availability for download of non-redundant sets of structurally annotated P-sites. Moreover, it features P3Dscan, a new functionality that allows the user to submit a protein structure and scan it against the 3D zones collected in the Phospho3D database. Phospho3D version 2.0 is available at: http://www.phospho3d.org/.
doi:10.1093/nar/gkq936
PMCID: PMC3013787  PMID: 20965970
7.  ELM: the status of the 2010 eukaryotic linear motif resource 
Nucleic Acids Research  2009;38(Database issue):D167-D180.
Linear motifs are short segments of multidomain proteins that provide regulatory functions independently of protein tertiary structure. Much of intracellular signalling passes through protein modifications at linear motifs. Many thousands of linear motif instances, most notably phosphorylation sites, have now been reported. Although clearly very abundant, linear motifs are difficult to predict de novo in protein sequences due to the difficulty of obtaining robust statistical assessments. The ELM resource at http://elm.eu.org/ provides an expanding knowledge base, currently covering 146 known motifs, with annotation that includes >1300 experimentally reported instances. ELM is also an exploratory tool for suggesting new candidates of known linear motifs in proteins of interest. Information about protein domains, protein structure and native disorder, cellular and taxonomic contexts is used to reduce or deprecate false positive matches. Results are graphically displayed in a ‘Bar Code’ format, which also displays known instances from homologous proteins through a novel ‘Instance Mapper’ protocol based on PHI-BLAST. ELM server output provides links to the ELM annotation as well as to a number of remote resources. Using the links, researchers can explore the motifs, proteins, complex structures and associated literature to evaluate whether candidate motifs might be worth experimental investigation.
doi:10.1093/nar/gkp1016
PMCID: PMC2808914  PMID: 19920119
8.  Evidence for the Concerted Evolution between Short Linear Protein Motifs and Their Flanking Regions 
PLoS ONE  2009;4(7):e6052.
Background
Linear motifs are short modules of protein sequences that play a crucial role in mediating and regulating many protein–protein interactions. The function of linear motifs strongly depends on the context, e.g. functional instances mainly occur inside flexible regions that are accessible for interaction. Sometimes linear motifs appear as isolated islands of conservation in multiple sequence alignments. However, they also occur in larger blocks of sequence conservation, suggesting an active role for the neighbouring amino acids.
Results
The evolution of regions flanking 116 functional linear motif instances was studied. The conservation of the amino acid sequence and order/disorder tendency of those regions was related to presence/absence of the instance. For the majority of the analysed instances, the pairs of sequences conserving the linear motif were also observed to maintain a similar local structural tendency and/or to have higher local sequence conservation when compared to pairs of sequences where one is missing the linear motif. Furthermore, those instances have a higher chance to co–evolve with the neighbouring residues in comparison to the distant ones. Those findings are supported by examples where the regulation of the linear motif–mediated interaction has been shown to depend on the modifications (e.g. phosphorylation) at neighbouring positions or is thought to benefit from the binding versatility of disordered regions.
Conclusion
The results suggest that flanking regions are relevant for linear motif–mediated interactions, both at the structural and sequence level. More interestingly, they indicate that the prediction of linear motif instances can be enriched with contextual information by performing a sequence analysis similar to the one presented here. This can facilitate the understanding of the role of these predicted instances in determining the protein function inside the broader context of the cellular network where they arise.
doi:10.1371/journal.pone.0006052
PMCID: PMC2702822  PMID: 19584925
9.  Systematic Discovery of In Vivo Phosphorylation Networks 
Cell  2007;129(7):1415-1426.
Summary
Protein kinases control cellular decision processes by phosphorylating specific substrates. Proteome-wide mapping has identified thousands of in vivo phosphorylation sites. However, systematically resolving which kinase targets each site is presently infeasible, due to the limited specificity of consensus motifs and the potential influence of contextual factors, such as protein scaffolds, localisation and expression, on cellular substrate specificity. We have therefore developed a computational method, NetworKIN, that augments motifs with context for kinases and phosphoproteins. This can pinpoint individual kinases responsible for specific in vivo phosphorylation events and yields a 2.5-fold improvement in the accuracy with which phosphorylation networks can be constructed. We show that context provides 60–80% of the computational capability to assign in vivo substrate specificity. Applying this approach to a DNA damage signalling network, we extend its cell-cycle regulation by showing that 53BP1 is a CDK1 substrate, show that Rad50 is phosphorylated by ATM kinase under genotoxic stress, and suggest novel roles of ATM in apoptosis. Finally, we present a scalable strategy to validate our predictions and use it to support the prediction that BCLAF1 is a GSK3 substrate.
doi:10.1016/j.cell.2007.05.052
PMCID: PMC2692296  PMID: 17570479
10.  KEPE—a motif frequently superimposed on sumoylation sites in metazoan chromatin proteins and transcription factors 
Bioinformatics  2008;25(1):1-5.
Motivation: We noted that the sumoylation site in C/EBP homologues is conserved beyond the canonical consensus sequence for sumoylation. Therefore, we investigated whether this pattern might define a more general protein motif.
Results: We undertook a survey of the human proteome using a regular expression based on the C/EBP motif. This revealed significant enrichment of the motif using different Gene Ontology terms (e.g. ‘transcription’) that pertain to the nucleus. When considering requirements for the motif to be functional (evolutionary conservation, structural accessibility of the motif and proper cell localization of the protein), more than 130 human proteins were retrieved from the UniProt/Swiss-Prot database. These candidates were particularly enriched in transcription factors, including FOS, JUN, Hif-1α, MLL2 and members of the KLF, MAF and NFATC families; chromatin modifiers like CHD-8, HDAC4 and DNA Top1; and the transcriptional regulatory kinases HIPK1 and HIPK2. The KEPEmotif appears to be restricted to the metazoan lineage and has three length variants—short, medium and long—which do not appear to interchange.
Contact: toby.gibson@embl.de
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btn594
PMCID: PMC2638927  PMID: 19033273
11.  Phospho.ELM: a database of phosphorylation sites—update 2008 
Nucleic Acids Research  2007;36(Database issue):D240-D244.
Phospho.ELM is a manually curated database of eukaryotic phosphorylation sites. The resource includes data collected from published literature as well as high-throughput data sets.
The current release of Phospho.ELM (version 7.0, July 2007) contains 4078 phospho-protein sequences covering 12 025 phospho-serine, 2362 phospho-threonine and 2083 phospho-tyrosine sites. The entries provide information about the phosphorylated proteins and the exact position of known phosphorylated instances, the kinases responsible for the modification (where known) and links to bibliographic references. The database entries have hyperlinks to easily access further information from UniProt, PubMed, SMART, ELM, MSD as well as links to the protein interaction databases MINT and STRING.
A new BLAST search tool, complementary to retrieval by keyword and UniProt accession number, allows users to submit a protein query (by sequence or UniProt accession) to search against the curated data set of phosphorylated peptides.
Phospho.ELM is available on line at: http://phospho.elm.eu.org
doi:10.1093/nar/gkm772
PMCID: PMC2238828  PMID: 17962309
12.  Phospho.ELM: A database of experimentally verified phosphorylation sites in eukaryotic proteins 
BMC Bioinformatics  2004;5:79.
Background
Post-translational phosphorylation is one of the most common protein modifications. Phosphoserine, threonine and tyrosine residues play critical roles in the regulation of many cellular processes. The fast growing number of research reports on protein phosphorylation points to a general need for an accurate database dedicated to phosphorylation to provide easily retrievable information on phosphoproteins.
Description
Phospho.ELM is a new resource containing experimentally verified phosphorylation sites manually curated from the literature and is developed as part of the ELM (Eukaryotic Linear Motif) resource. Phospho.ELM constitutes the largest searchable collection of phosphorylation sites available to the research community. The Phospho.ELM entries store information about substrate proteins with the exact positions of residues known to be phosphorylated by cellular kinases. Additional annotation includes literature references, subcellular compartment, tissue distribution, and information about the signaling pathways involved as well as links to the molecular interaction database MINT. Phospho.ELM version 2.0 contains 1703 phosphorylation site instances for 556 phosphorylated proteins.
Conclusion
Phospho.ELM will be a valuable tool both for molecular biologists working on protein phosphorylation sites and for bioinformaticians developing computational predictions on the specificity of phosphorylation reactions.
doi:10.1186/1471-2105-5-79
PMCID: PMC449700  PMID: 15212693
post-transcriptional modification; protein kinase; bioinformatics
13.  ELM server: a new resource for investigating short functional sites in modular eukaryotic proteins 
Nucleic Acids Research  2003;31(13):3625-3630.
Multidomain proteins predominate in eukaryotic proteomes. Individual functions assigned to different sequence segments combine to create a complex function for the whole protein. While on-line resources are available for revealing globular domains in sequences, there has hitherto been no comprehensive collection of small functional sites/motifs comparable to the globular domain resources, yet these are as important for the function of multidomain proteins. Short linear peptide motifs are used for cell compartment targeting, protein–protein interaction, regulation by phosphorylation, acetylation, glycosylation and a host of other post-translational modifications. ELM, the Eukaryotic Linear Motif server at http://elm.eu.org/, is a new bioinformatics resource for investigating candidate short non-globular functional motifs in eukaryotic proteins, aiming to fill the void in bioinformatics tools. Sequence comparisons with short motifs are difficult to evaluate because the usual significance assessments are inappropriate. Therefore the server is implemented with several logical filters to eliminate false positives. Current filters are for cell compartment, globular domain clash and taxonomic range. In favourable cases, the filters can reduce the number of retained matches by an order of magnitude or more.
PMCID: PMC168952  PMID: 12824381

Results 1-13 (13)