%0 Journal Article %J Nucleic Acids Res %D 2023 %T ELM-the Eukaryotic Linear Motif resource-2024 update. %A Manjeet Kumar %A Michael, Sushama %A Jesús Alvarado-Valverde %A Zeke, András %A Tamas Lazar %A Juliana Glavina %A Eszter Nagy-Kanta %A Juan Mac Donagh %A Zsofia E Kalman %A Stefano Pascarelli %A Nicolas Palopoli %A László Dobson %A Carmen Florencia Suarez %A Kim Van Roey %A Izabella Krystkowiak %A Juan Esteban Griffin %A Nagpal, Anurag %A Rajesh Bhardwaj %A Francesca Diella %A Mészáros, Bálint %A Kellie Dean %A Norman E Davey %A Rita Pancsa %A Lucia B Chemes %A Toby J Gibson %X

Short Linear Motifs (SLiMs) are the smallest structural and functional components of modular eukaryotic proteins. They are also the most abundant, especially when considering post-translational modifications. As well as being found throughout the cell as part of regulatory processes, SLiMs are extensively mimicked by intracellular pathogens. At the heart of the Eukaryotic Linear Motif (ELM) Resource is a representative (not comprehensive) database. The ELM entries are created by a growing community of skilled annotators and provide an introduction to linear motif functionality for biomedical researchers. The 2024 ELM update includes 346 novel motif instances in areas ranging from innate immunity to both protein and RNA degradation systems. In total, 39 classes of newly annotated motifs have been added, and another 17 existing entries have been updated in the database. The 2024 ELM release now includes 356 motif classes incorporating 4283 individual motif instances manually curated from 4274 scientific publications and including >700 links to experimentally determined 3D structures. In a recent development, the InterPro protein module resource now also includes ELM data. ELM is available at: http://elm.eu.org.

%B Nucleic Acids Res %8 2023 Nov 14 %G eng %R 10.1093/nar/gkad1058 %0 Journal Article %J Nat Methods %D 2023 %T Minimum information guidelines for experiments structurally characterizing intrinsically disordered protein regions. %A Mészáros, Bálint %A András Hatos %A Nicolas Palopoli %A Federica Quaglia %A Edoardo Salladini %A Kim Van Roey %A Arthanari, Haribabu %A Zsuzsanna Dosztányi %A Isabella C Felli %A Patrick D Fischer %A Jeffrey C Hoch %A Cy M Jeffries %A Sonia Longhi %A Emiliano Maiani %A Sandra Orchard %A Rita Pancsa %A Elena Papaleo %A Roberta Pierattelli %A Damiano Piovesan %A Iva Pritisanac %A Luiggi Tenorio %A Thibault Viennet %A Peter Tompa %A Wim Vranken %A Silvio C E Tosatto %A Norman E Davey %K Intrinsically Disordered Proteins %K Protein Conformation %X

An unambiguous description of an experiment, and the subsequent biological observation, is vital for accurate data interpretation. Minimum information guidelines define the fundamental complement of data that can support an unambiguous conclusion based on experimental observations. We present the Minimum Information About Disorder Experiments (MIADE) guidelines to define the parameters required for the wider scientific community to understand the findings of an experiment studying the structural properties of intrinsically disordered regions (IDRs). MIADE guidelines provide recommendations for data producers to describe the results of their experiments at source, for curators to annotate experimental data to community resources and for database developers maintaining community resources to disseminate the data. The MIADE guidelines will improve the interpretability of experimental results for data consumers, facilitate direct data submission, simplify data curation, improve data exchange among repositories and standardize the dissemination of the key metadata on an IDR experiment by IDR data sources.

%B Nat Methods %V 20 %8 2023 Sep %G eng %N 9 %R 10.1038/s41592-023-01915-x %0 Report %D 2023 %T Orphanet vertaling: activiteitenrapport (2022) %A Kim Van Roey %K Orphanet %K Rare diseases %I Sciensano %C Brussels, Belgium %P 19 %8 02/2023 %G eng %0 Report %D 2022 %T Orphanet vertaling: activiteitenrapport (2021) %A Kim Van Roey %A Elfriede Swinnen %K Orphanet %K Rare diseases %I Sciensano %C Brussels, Belgium %P 17 %8 02/2022 %G eng %0 Report %D 2021 %T Orphanet vertaling: activiteitenrapport (2020) %A Kim Van Roey %A Elfriede Swinnen %K Orphanet %K Rare diseases %I Sciensano %C Brussels, Belgium %P 17 %8 04/2021 %G eng %0 Journal Article %J Methods Mol Biol %D 2020 %T How to Annotate and Submit a Short Linear Motif to the Eukaryotic Linear Motif Resource. %A Marc Gouw %A Jesús Alvarado-Valverde %A Jelena Čalyševa %A Francesca Diella %A Manjeet Kumar %A Michael, Sushama %A Kim Van Roey %A Holger Dinkel %A Toby J Gibson %X

Over the past few years, it has become apparent that approximately 35% of the human proteome consists of intrinsically disordered regions. Many of these disordered regions are rich in short linear motifs (SLiMs) which mediate protein-protein interactions. Although these motifs are short and often partially conserved, they are involved in many important aspects of protein function, including cleavage, targeting, degradation, docking, phosphorylation, and other posttranslational modifications. The Eukaryotic Linear Motif resource (ELM) was established over 15 years ago as a repository to store and catalogue the scientific discoveries of motifs. Each motif in the database is annotated and curated manually, based on the experimental evidence gathered from publications. The entries themselves are submitted to ELM by filling in two annotation templates designed for motif class and motif instance annotation. In this protocol, we describe the steps involved in annotating new motifs and how to submit them to ELM.

%B Methods Mol Biol %V 2141 %8 2020 %G eng %R 10.1007/978-1-0716-0524-0_4 %0 Journal Article %J Nat Commun %D 2019 %T Capturing variation impact on molecular interactions in the IMEx Consortium mutations data set. %A N Del-Toro %A M Duesbury %A M Koch %A L Perfetto %A A Shrivastava %A D Ochoa %A O Wagih %A J Piñero %A M Kotlyar %A C Pastrello %A P Beltrao %A L I Furlong %A I Jurisica %A H Hermjakob %A S Orchard %A P Porras %K Amino Acid Substitution %K Animals %K disease %K Genetic Variation %K Humans %K Molecular Sequence Annotation %K Point Mutation %K Protein Interaction Maps %X

The current wealth of genomic variation data identified at nucleotide level presents the challenge of understanding by which mechanisms amino acid variation affects cellular processes. These effects may manifest as distinct phenotypic differences between individuals or result in the development of disease. Physical interactions between molecules are the linking steps underlying most, if not all, cellular processes. Understanding the effects that sequence variation has on a molecule's interactions is a key step towards connecting mechanistic characterization of nonsynonymous variation to phenotype. We present an open access resource created over 14 years by IMEx database curators, featuring 28,000 annotations describing the effect of small sequence changes on physical protein interactions. We describe how this resource was built, the formats in which the data is provided and offer a descriptive analysis of the data set. The data set is publicly available through the IntAct website and is enhanced with every monthly release.

%B Nat Commun %V 10 %8 2019 01 02 %G eng %N 1 %R 10.1038/s41467-018-07709-6 %0 Report %D 2019 %T Orphanet vertaling: activiteitenrapport (2018-2019) %A Kim Van Roey %A Elfriede Swinnen %A Kris Doggen %K Orphanet %K Rare diseases %I Sciensano %C Brussels, Belgium %P 17 %8 12/2019 %G eng %M D/2020/14.440/92; D/2020/14.440/94; D/2020/14.440/93 %0 Journal Article %J BMC Bioinformatics %D 2018 %T Encompassing new use cases - level 3.0 of the HUPO-PSI format for molecular interactions. %A Sivade M Dumousseau %A D Alonso-López %A M Ammari %A G Bradley %A N H Campbell %A A Ceol %A G Cesareni %A C Combe %A J De Las Rivas %A N Del-Toro %A J Heimbach %A H Hermjakob %A I Jurisica %A M Koch %A L Licata %A R C Lovering %A D J Lynn %A B H M Meldal %A G Micklem %A S Panni %A P Porras %A S Ricard-Blum %A B Roechert %A L Salwinski %A A Shrivastava %A J Sullivan %A N Thierry-Mieg %A Y Yehudi %A Kim Van Roey %A S Orchard %K Databases, Protein %K Humans %K Mutation %K Protein Interaction Maps %K Proteome %K Proteomics %K Systems Biology %X

BACKGROUND: Systems biologists study interaction data to understand the behaviour of whole cell systems, and their environment, at a molecular level. In order to effectively achieve this goal, it is critical that researchers have high quality interaction datasets available to them, in a standard data format, and also a suite of tools with which to analyse such data and form experimentally testable hypotheses from them. The PSI-MI XML standard interchange format was initially published in 2004, and expanded in 2007 to enable the download and interchange of molecular interaction data. PSI-XML2.5 was designed to describe experimental data and to date has fulfilled this basic requirement. However, new use cases have arisen that the format cannot properly accommodate. These include data abstracted from more than one publication such as allosteric/cooperative interactions and protein complexes, dynamic interactions and the need to link kinetic and affinity data to specific mutational changes.

RESULTS: The Molecular Interaction workgroup of the HUPO-PSI has extended the existing, well-used XML interchange format for molecular interaction data to meet new use cases and enable the capture of new data types, following extensive community consultation. PSI-MI XML3.0 expands the capabilities of the format beyond simple experimental data, with a concomitant update of the tool suite which serves this format. The format has been implemented by key data producers such as the International Molecular Exchange (IMEx) Consortium of protein interaction databases and the Complex Portal.

CONCLUSIONS: PSI-MI XML3.0 has been developed by the data producers, data users, tool developers and database providers who constitute the PSI-MI workgroup. This group now actively supports PSI-MI XML2.5 as the main interchange format for experimental data, PSI-MI XML3.0 which additionally handles more complex data types, and the simpler, tab-delimited MITAB2.5, 2.6 and 2.7 for rapid parsing and download.

%B BMC Bioinformatics %V 19 %8 2018 04 11 %G eng %N 1 %R 10.1186/s12859-018-2118-1 %0 Journal Article %J Nucleic Acids Res %D 2018 %T The eukaryotic linear motif resource - 2018 update. %A Marc Gouw %A Michael, Sushama %A Hugo Sámano-Sánchez %A Manjeet Kumar %A András Zeke %A Benjamin Lang %A Benoit Bely %A Lucia B Chemes %A Norman E Davey %A Deng, Ziqi %A Francesca Diella %A Clara-Marie Gürth %A Ann-Kathrin Huber %A Stefan Kleinsorg %A Lara S Schlegel %A Nicolás Palopoli %A Kim Van Roey %A Brigitte Altenberg %A Attila Reményi %A Holger Dinkel %A Toby J Gibson %K Amino Acid Motifs %K Animals %K bacteria %K Binding Sites %K Cell Cycle %K Databases, Protein %K Eukaryotic Cells %K Fungi %K Host-Pathogen Interactions %K Humans %K Internet %K Models, Molecular %K Molecular Sequence Annotation %K Plants %K Protein Binding %K Protein Conformation, alpha-Helical %K Protein Conformation, beta-Strand %K Protein Interaction Domains and Motifs %K Proteins %K SOFTWARE %K Viruses %X

Short linear motifs (SLiMs) are protein binding modules that play major roles in almost all cellular processes. SLiMs are short, often highly degenerate, difficult to characterize and hard to detect. The eukaryotic linear motif (ELM) resource (elm.eu.org) is dedicated to SLiMs, consisting of a manually curated database of over 275 motif classes and over 3000 motif instances, and a pipeline to discover candidate SLiMs in protein sequences. For 15 years, ELM has been one of the major resources for motif research. In this database update, we present the latest additions to the database including 32 new motif classes, and new features including Uniprot and Reactome integration. Finally, to help provide cellular context, we present some biological insights about SLiMs in the cell cycle, as targets for bacterial pathogenicity and their functionality in the human kinome.

%B Nucleic Acids Res %V 46 %8 2018 01 04 %G eng %N D1 %R 10.1093/nar/gkx1077 %0 Journal Article %J Curr Protoc Bioinformatics %D 2017 %T Exploring Short Linear Motifs Using the ELM Database and Tools. %A Marc Gouw %A Hugo Sámano-Sánchez %A Kim Van Roey %A Francesca Diella %A Toby J Gibson %A Holger Dinkel %K Amino Acid Motifs %K Computational Biology %K Databases, Protein %K Eukaryota %K Protein Domains %K Proteins %X

The Eukaryotic Linear Motif (ELM) resource is dedicated to the characterization and prediction of short linear motifs (SLiMs). SLiMs are compact, degenerate peptide segments found in many proteins and essential to almost all cellular processes. However, despite their abundance, SLiMs remain largely uncharacterized. The ELM database is a collection of manually annotated SLiM instances curated from experimental literature. In this article we illustrate how to browse and search the database for curated SLiM data, and cover the different types of data integrated in the resource. We also cover how to use this resource in order to predict SLiMs in known as well as novel proteins, and how to interpret the results generated by the ELM prediction pipeline. The ELM database is a very rich resource, and in the following protocols we give helpful examples to demonstrate how this knowledge can be used to improve your own research. © 2017 by John Wiley & Sons, Inc.

%B Curr Protoc Bioinformatics %V 58 %8 2017 06 27 %G eng %R 10.1002/cpbi.26 %0 Journal Article %J Nucleic Acids Res %D 2016 %T ELM 2016--data update and new functionality of the eukaryotic linear motif resource. %A Holger Dinkel %A Kim Van Roey %A Michael, Sushama %A Manjeet Kumar %A Bora Uyar %A Brigitte Altenberg %A Vladislava Milchevskaya %A Melanie Schneider %A Helen Kühn %A Annika Behrendt %A Sophie Luise Dahl %A Victoria Damerell %A Sandra Diebel %A Sara Kalman %A Steffen Klein %A Arne C Knudsen %A Christina Mäder %A Sabina Merrill %A Angelina Staudt %A Vera Thiel %A Lukas Welti %A Norman E Davey %A Francesca Diella %A Toby J Gibson %K Amino Acid Motifs %K Databases, Protein %K Eukaryota %K Internet %K Signal Transduction %K SOFTWARE %X

The Eukaryotic Linear Motif (ELM) resource (http://elm.eu.org) is a manually curated database of short linear motifs (SLiMs). In this update, we present the latest additions to this resource, along with more improvements to the web interface. ELM 2016 contains more than 240 different motif classes with over 2700 experimentally validated instances, manually curated from more than 2400 scientific publications. In addition, more data have been made available as individually searchable pages and are downloadable in various formats.

%B Nucleic Acids Res %V 44 %8 2016 Jan 04 %G eng %N D1 %R 10.1093/nar/gkv1291 %0 Report %D 2016 %T Etude de faisabilité : développement et implémentation d'un système de controle de qualité dans les 8 centres de génétique humaine et d'un registre de tests de génétique effectués dans ces centres %A Fabienne Van Aelst %A Jean-Bernard Beaudry %A Kim Van Roey %I WIV-ISP %C Brussels, Belgium %P 117 %8 Aug 2016 %G eng %0 Report %D 2016 %T Haalbaarheidsstudie: ontwikkeling en implementatie van een kwaliteitscontrolesysteem in de 8 centra voor menselijke genetica en de creatie van een register van genetische testen die in deze centra worden uitgevoerd %A Fabienne Van Aelst %A Jean-Bernard Beaudry %A Kim Van Roey %I WIV-ISP %C Brussels, Belgium %P 117 %8 Aug 2016 %G eng %M D/2016/2505/30 %0 Journal Article %J Cell Commun Signal %D 2015 %T Experimental detection of short regulatory motifs in eukaryotic proteins: tips for good practice as well as for bad. %A Toby J Gibson %A Holger Dinkel %A Kim Van Roey %A Francesca Diella %K Amino Acid Motifs %K Animals %K Computational Biology %K Eukaryota %K Genetic Testing %K Humans %K Proteins %X

It has become clear in outline though not yet in detail how cellular regulatory and signalling systems are constructed. The essential machines are protein complexes that effect regulatory decisions by undergoing internal changes of state. Subcomponents of these cellular complexes are assembled into molecular switches. Many of these switches employ one or more short peptide motifs as toggles that can move between one or more sites within the switch system, the simplest being on-off switches. Paradoxically, these motif modules (termed short linear motifs or SLiMs) are both hugely abundant but difficult to research. So despite the many successes in identifying short regulatory protein motifs, it is thought that only the "tip of the iceberg" has been exposed. Experimental and bioinformatic motif discovery remain challenging and error prone. The advice presented in this article is aimed at helping researchers to uncover genuine protein motifs, whilst avoiding the pitfalls that lead to reports of false discovery.

%B Cell Commun Signal %V 13 %8 2015 Nov 18 %G eng %R 10.1186/s12964-015-0121-y %0 Journal Article %J Cell Commun Signal %D 2015 %T Motif co-regulation and co-operativity are common mechanisms in transcriptional, post-transcriptional and post-translational regulation. %A Kim Van Roey %A Norman E Davey %K Amino Acid Motifs %K Animals %K Dna %K Humans %K Protein Processing, Post-Translational %K Proteins %K Rna %K RNA Processing, Post-Transcriptional %K Transcription, Genetic %X

A substantial portion of the regulatory interactions in the higher eukaryotic cell are mediated by simple sequence motifs in the regulatory segments of genes and (pre-)mRNAs, and in the intrinsically disordered regions of proteins. Although these regulatory modules are physicochemically distinct, they share an evolutionary plasticity that has facilitated a rapid growth of their use and resulted in their ubiquity in complex organisms. The ease of motif acquisition simplifies access to basal housekeeping functions, facilitates the co-regulation of multiple biomolecules allowing them to respond in a coordinated manner to changes in the cell state, and supports the integration of multiple signals for combinatorial decision-making. Consequently, motifs are indispensable for temporal, spatial, conditional and basal regulation at the transcriptional, post-transcriptional and post-translational level. In this review, we highlight that many of the key regulatory pathways of the cell are recruited by motifs and that the ease of motif acquisition has resulted in large networks of co-regulated biomolecules. We discuss how co-operativity allows simple static motifs to perform the conditional regulation that underlies decision-making in higher eukaryotic biological systems. We observe that each gene and its products have a unique set of DNA, RNA or protein motifs that encode a regulatory program to define the logical circuitry that guides the life cycle of these biomolecules, from transcription to degradation. Finally, we contrast the regulatory properties of protein motifs and the regulatory elements of DNA and (pre-)mRNAs, advocating that co-regulation, co-operativity, and motif-driven regulatory programs are common mechanisms that emerge from the use of simple, evolutionarily plastic regulatory modules.

%B Cell Commun Signal %V 13 %8 2015 Dec 01 %G eng %R 10.1186/s12964-015-0123-9 %0 Journal Article %J Nucleic Acids Res %D 2014 %T The eukaryotic linear motif resource ELM: 10 years and counting. %A Holger Dinkel %A Kim Van Roey %A Michael, Sushama %A Norman E Davey %A Robert J Weatheritt %A Diana Born %A Tobias Speck %A Daniel Krüger %A Gleb Grebnev %A Marta Kuban %A Marta Strumillo %A Bora Uyar %A Aidan Budd %A Brigitte Altenberg %A Markus Seiler %A Lucia B Chemes %A Juliana Glavina %A Ignacio E Sánchez %A Francesca Diella %A Toby J Gibson %K Amino Acid Motifs %K Databases, Protein %K Internet %K Multiprotein Complexes %K Protein Interaction Domains and Motifs %X

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.

%B Nucleic Acids Res %V 42 %8 2014 Jan %G eng %N Database issue %R 10.1093/nar/gkt1047 %0 Journal Article %J Nucleic Acids Res %D 2014 %T The MIntAct project--IntAct as a common curation platform for 11 molecular interaction databases. %A Sandra Orchard %A Mais Ammari %A Bruno Aranda %A Lionel Breuza %A Leonardo Briganti %A Fiona Broackes-Carter %A Nancy H Campbell %A Chavali, Gayatri %A Carol Chen %A Noemi del-Toro %A Margaret Duesbury %A Marine Dumousseau %A Eugenia Galeota %A Ursula Hinz %A Marta Iannuccelli %A Sruthi Jagannathan %A Rafael Jimenez %A Jyoti Khadake %A Astrid Lagreid %A Luana Licata %A Ruth C Lovering %A Birgit Meldal %A Anna N Melidoni %A Mila Milagros %A Daniele Peluso %A Livia Perfetto %A Pablo Porras %A Raghunath, Arathi %A Sylvie Ricard-Blum %A Bernd Roechert %A Andre Stutz %A Michael Tognolli %A Kim Van Roey %A Gianni Cesareni %A Hermjakob, Henning %K Databases, Protein %K Internet %K Protein Interaction Mapping %K SOFTWARE %X

IntAct (freely available at http://www.ebi.ac.uk/intact) is an open-source, open data molecular interaction database populated by data either curated from the literature or from direct data depositions. IntAct has developed a sophisticated web-based curation tool, capable of supporting both IMEx- and MIMIx-level curation. This tool is now utilized by multiple additional curation teams, all of whom annotate data directly into the IntAct database. Members of the IntAct team supply appropriate levels of training, perform quality control on entries and take responsibility for long-term data maintenance. Recently, the MINT and IntAct databases decided to merge their separate efforts to make optimal use of limited developer resources and maximize the curation output. All data manually curated by the MINT curators have been moved into the IntAct database at EMBL-EBI and are merged with the existing IntAct dataset. Both IntAct and MINT are active contributors to the IMEx consortium (http://www.imexconsortium.org).

%B Nucleic Acids Res %V 42 %8 2014 Jan %G eng %N Database issue %R 10.1093/nar/gkt1115 %0 Journal Article %J Chem Rev %D 2014 %T Short linear motifs: ubiquitous and functionally diverse protein interaction modules directing cell regulation. %A Kim Van Roey %A Bora Uyar %A Robert J Weatheritt %A Holger Dinkel %A Markus Seiler %A Aidan Budd %A Toby J Gibson %A Norman E Davey %K Amino Acid Motifs %K disease %K Humans %K Protein Processing, Post-Translational %K Protein Structure, Tertiary %B Chem Rev %V 114 %8 2014 Jul 09 %G eng %N 13 %R 10.1021/cr400585q %0 Journal Article %J Database (Oxford) %D 2013 %T Capturing cooperative interactions with the PSI-MI format. %A Kim Van Roey %A Sandra Orchard %A Samuel Kerrien %A Marine Dumousseau %A Sylvie Ricard-Blum %A Hermjakob, Henning %A Toby J Gibson %K Allosteric Regulation %K Cell Cycle Proteins %K Cyclin A %K Cyclin-Dependent Kinase 2 %K Databases, Protein %K Humans %K Models, Molecular %K Molecular Sequence Annotation %K Phosphorylation %K Protein Binding %K Protein Interaction Mapping %K Proteomics %X

The complex biological processes that control cellular function are mediated by intricate networks of molecular interactions. Accumulating evidence indicates that these interactions are often interdependent, thus acting cooperatively. Cooperative interactions are prevalent in and indispensible for reliable and robust control of cell regulation, as they underlie the conditional decision-making capability of large regulatory complexes. Despite an increased focus on experimental elucidation of the molecular details of cooperative binding events, as evidenced by their growing occurrence in literature, they are currently lacking from the main bioinformatics resources. One of the contributing factors to this deficiency is the lack of a computer-readable standard representation and exchange format for cooperative interaction data. To tackle this shortcoming, we added functionality to the widely used PSI-MI interchange format for molecular interaction data by defining new controlled vocabulary terms that allow annotation of different aspects of cooperativity without making structural changes to the underlying XML schema. As a result, we are able to capture cooperative interaction data in a structured format that is backward compatible with PSI-MI-based data and applications. This will facilitate the storage, exchange and analysis of cooperative interaction data, which in turn will advance experimental research on this fundamental principle in biology.

%B Database (Oxford) %V 2013 %8 2013 %G eng %R 10.1093/database/bat066 %0 Journal Article %J Sci Signal %D 2013 %T The switches.ELM resource: a compendium of conditional regulatory interaction interfaces. %A Kim Van Roey %A Holger Dinkel %A Robert J Weatheritt %A Toby J Gibson %A Norman E Davey %K Amino Acid Motifs %K Amino Acid Sequence %K Binding Sites %K Databases, Protein %K Molecular Sequence Data %K Protein Binding %K Protein Interaction Domains and Motifs %K Protein Interaction Mapping %K Protein Interaction Maps %K Protein Processing, Post-Translational %K Proteins %K Sequence Homology, Amino Acid %K Signal Transduction %X

Short linear motifs (SLiMs) are protein interaction sites that play an important role in cell regulation by controlling protein activity, localization, and local abundance. The functionality of a SLiM can be modulated in a context-dependent manner to induce a gain, loss, or exchange of binding partners, which will affect the function of the SLiM-containing protein. As such, these conditional interactions underlie molecular decision-making in cell signaling. We identified multiple types of pre- and posttranslational switch mechanisms that can regulate the function of a SLiM and thereby control its interactions. The collected examples of experimentally characterized SLiM-based switch mechanisms were curated in the freely accessible switches.ELM resource (http://switches.elm.eu.org). On the basis of these examples, we defined and integrated rules to analyze SLiMs for putative regulatory switch mechanisms. We applied these rules to known validated SLiMs, providing evidence that more than half of these are likely to be pre- or posttranslationally regulated. In addition, we showed that posttranslationally modified sites are enriched around SLiMs, which enables cooperative and integrative regulation of protein interaction interfaces. We foresee switches.ELM complementing available resources to extend our knowledge of the molecular mechanisms underlying cell signaling.

%B Sci Signal %V 6 %8 2013 Apr 02 %G eng %N 269 %R 10.1126/scisignal.2003345 %0 Journal Article %J Mol Biosyst %D 2012 %T Attributes of short linear motifs. %A Norman E Davey %A Kim Van Roey %A Robert J Weatheritt %A Grischa Toedt %A Bora Uyar %A Brigitte Altenberg %A Aidan Budd %A Francesca Diella %A Holger Dinkel %A Toby J Gibson %K Amino Acid Motifs %K Amino acids %K Animals %K Conserved Sequence %K Databases, Protein %K Evolution, Molecular %K Humans %K Hydrophobic and Hydrophilic Interactions %K Protein Folding %K Protein Structure, Tertiary %K Proteins %K Repetitive Sequences, Amino Acid %K Sequence Alignment %X

Traditionally, protein-protein interactions were thought to be mediated by large, structured domains. However, it has become clear that the interactome comprises a wide range of binding interfaces with varying degrees of flexibility, ranging from rigid globular domains to disordered regions that natively lack structure. Enrichment for disorder in highly connected hub proteins and its correlation with organism complexity hint at the functional importance of disordered regions. Nevertheless, they have not yet been extensively characterised. Shifting the attention from globular domains to disordered regions of the proteome might bring us closer to elucidating the dense and complex connectivity of the interactome. An important class of disordered interfaces are the compact mono-partite, short linear motifs (SLiMs, or eukaryotic linear motifs (ELMs)). They are evolutionarily plastic and interact with relatively low affinity due to the limited number of residues that make direct contact with the binding partner. These features confer to SLiMs the ability to evolve convergently and mediate transient interactions, which is imperative to network evolution and to maintain robust cell signalling, respectively. The ability to discriminate biologically relevant SLiMs by means of different attributes will improve our understanding of the complexity of the interactome and aid development of bioinformatics tools for motif discovery. In this paper, the curated instances currently available in the Eukaryotic Linear Motif (ELM) database are analysed to provide a clear overview of the defining attributes of SLiMs. These analyses suggest that functional SLiMs have higher levels of conservation than their surrounding residues, frequently evolve convergently, preferentially occur in disordered regions and often form a secondary structure when bound to their interaction partner. These results advocate searching for small groupings of residues in disordered regions with higher relative conservation and a propensity to form the secondary structure. Finally, the most interesting conclusions are examined in regard to their functional consequences.

%B Mol Biosyst %V 8 %8 2012 Jan %G eng %N 1 %R 10.1039/c1mb05231d %0 Journal Article %J Nucleic Acids Res %D 2012 %T ELM--the database of eukaryotic linear motifs. %A Holger Dinkel %A Michael, Sushama %A Robert J Weatheritt %A Norman E Davey %A Kim Van Roey %A Brigitte Altenberg %A Grischa Toedt %A Bora Uyar %A Markus Seiler %A Aidan Budd %A Lisa Jödicke %A Marcel A Dammert %A Christian Schroeter %A Maria Hammer %A Tobias Schmidt %A Peter Jehl %A Caroline McGuigan %A Magdalena Dymecka %A Claudia Chica %A Katja Luck %A Allegra Via %A Andrew Chatr-Aryamontri %A Niall Haslam %A Gleb Grebnev %A Richard J Edwards %A Michel O Steinmetz %A Heike Meiselbach %A Francesca Diella %A Toby J Gibson %K Amino Acid Motifs %K Computer Graphics %K Databases, Protein %K disease %K Eukaryota %K Sequence Analysis, Protein %K User-Computer Interface %K Viral Proteins %X

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.

%B Nucleic Acids Res %V 40 %8 2012 Jan %G eng %N Database issue %R 10.1093/nar/gkr1064 %0 Journal Article %J Curr Opin Struct Biol %D 2012 %T Motif switches: decision-making in cell regulation. %A Kim Van Roey %A Toby J Gibson %A Norman E Davey %K Amino Acid Motifs %K Animals %K Eukaryotic Cells %K Humans %K Models, Biological %K Protein Binding %K Protein Interaction Domains and Motifs %K Proteins %X

Tight regulation of gene products from transcription to protein degradation is required for reliable and robust control of eukaryotic cell physiology. Many of the mechanisms directing cell regulation rely on proteins detecting the state of the cell through context-dependent, tuneable interactions. These interactions underlie the ability of proteins to make decisions by combining regulatory information encoded in a protein's expression level, localisation and modification state. This raises the question, how do proteins integrate available information to correctly make decisions? Over the past decade pioneering work on the nature and function of intrinsically disordered protein regions has revealed many elegant switching mechanisms that underlie cell signalling and regulation, prompting a reevaluation of their role in cooperative decision-making.

%B Curr Opin Struct Biol %V 22 %8 2012 Jun %G eng %N 3 %R 10.1016/j.sbi.2012.03.004 %0 Thesis %D 2009 %T MTAC, a pancreatic islet-specific HMG-box protein isolated as a suppressor of a glucose-sensing deficient yeast mutant %A Kim Van Roey %P 212 %8 09/01/2009 %G eng %0 Journal Article %J Biochem Soc Trans %D 2005 %T Nutrient sensing systems for rapid activation of the protein kinase A pathway in yeast. %A J M Thevelein %A R Geladé %A I Holsbeeks %A O Lagatie %A Y Popova %A F Rolland %A F Stolz %A van de Velde, S %A P Van Dijck %A P Vandormael %A A Van Nuland %A Kim Van Roey %A G Van Zeebroeck %A B Yan %K Cyclic AMP-Dependent Protein Kinases %K Enzyme Activation %K Glucose %K Membrane Transport Proteins %K Phosphates %K Phosphorylation %K Saccharomyces cerevisiae %K Sucrose %X

The cAMP-protein kinase A (PKA) pathway in the yeast Saccharomyces cerevisiae controls a variety of properties that depend on the nutrient composition of the medium. High activity of the pathway occurs in the presence of rapidly fermented sugars like glucose or sucrose, but only as long as growth is maintained. Growth arrest of fermenting cells or growth on a respiratory carbon source, like glycerol or ethanol, is associated with low activity of the PKA pathway. We have studied how different nutrients trigger rapid activation of the pathway. Glucose and sucrose activate cAMP synthesis through a G-protein-coupled receptor system, consisting of the GPCR Gpr1, the Galpha protein Gpa2 and its RGS protein Rgs2. Glucose is also sensed intracellularly through its phosphorylation. Specific mutations in Gpr1 abolish glucose but not sucrose signalling. Activation of the PKA pathway by addition of a nitrogen source or phosphate to nitrogen- or phosphate-starved cells, respectively, is not mediated by an increase in cAMP. Activation by amino acids is triggered by the general amino acid permease Gap1, which functions as a transporter/receptor. Short truncation of the C-terminus results in constitutively activating alleles. Activation by ammonium uses the ammonium permeases Mep1 and Mep2 as receptor. Specific point mutations in Mep2 uncouple signalling from transport. Activation by phosphate is triggered a.o. by the Pho84 phosphate permease. Several mutations in Pho84 separating transport and signalling or triggering constitutive activation have been obtained.

%B Biochem Soc Trans %V 33 %8 2005 Feb %G eng %N Pt 1 %R 10.1042/BST0330253 %0 Book %D 2003 %T Genomics and evolution of Metazoan Ga proteins %A Kim Van Roey %A M Derks %A J Poels %A J Vanden Broeck %8 2003 %@ 1-59033-960-6 %G eng %& 125