Akdel, M.
Pires, D.E.
Pardo, E.P.
Jänes, J.
Zalevsky, A.O.
Mészáros, B.
Bryant, P.
Good, L.L.
Laskowski, R.A.
Pozzati, G.
Shenoy, A.
Zhu, W.
Kundrotas, P.
Serra, V.R.
Rodrigues, C.H.
Dunham, A.S.
Burke, D.
Borkakoti, N.
Velankar, S.
Frost, A.
Basquin, J.
Lindorff-Larsen, K.
Bateman, A.
Kajava, A.V.
Valencia, A.
Ovchinnikov, S.
Durairaj, J.
Ascher, D.B.
Thornton, J.M.
Davey, N.E.
Stein, A.
Elofsson, A.
Croll, T.I.
Beltrao, P.
(2022). A structural biology community assessment of AlphaFold2 applications. Nature structural & molecular biology,
Vol.29
(11),
pp. 1056-1067.
show abstract
AbstractMost proteins fold into 3D structures that determine how they function and orchestrate the biological processes of the cell. Recent developments in computational methods for protein structure predictions have reached the accuracy of experimentally determined models. Although this has been independently verified, the implementation of these methods across structural-biology applications remains to be tested. Here, we evaluate the use of AlphaFold2 (AF2) predictions in the study of characteristic structural elements; the impact of missense variants; function and ligand binding site predictions; modeling of interactions; and modeling of experimental structural data. For 11 proteomes, an average of 25% additional residues can be confidently modeled when compared with homology modeling, identifying structural features rarely seen in the Protein Data Bank. AF2-based predictions of protein disorder and complexes surpass dedicated tools, and AF2 models can be used across diverse applications equally well compared with experimentally determined structures, when the confidence metrics are critically considered. In summary, we find that these advances are likely to have a transformative impact in structural biology and broader life-science research..
Necci, M.
Piovesan, D.
Tosatto, S.C.
(2021). Critical assessment of protein intrinsic disorder prediction. Nature methods,
Vol.18
(5),
pp. 472-481.
show abstract
AbstractIntrinsically disordered proteins, defying the traditional protein structure–function paradigm, are a challenge to study experimentally. Because a large part of our knowledge rests on computational predictions, it is crucial that their accuracy is high. The Critical Assessment of protein Intrinsic Disorder prediction (CAID) experiment was established as a community-based blind test to determine the state of the art in prediction of intrinsically disordered regions and the subset of residues involved in binding. A total of 43 methods were evaluated on a dataset of 646 proteins from DisProt. The best methods use deep learning techniques and notably outperform physicochemical methods. The top disorder predictor has Fmax = 0.483 on the full dataset and Fmax = 0.792 following filtering out of bona fide structured regions. Disordered binding regions remain hard to predict, with Fmax = 0.231. Interestingly, computing times among methods can vary by up to four orders of magnitude..
Kruse, T.
Benz, C.
Garvanska, D.H.
Lindqvist, R.
Mihalic, F.
Coscia, F.
Inturi, R.
Sayadi, A.
Simonetti, L.
Nilsson, E.
Ali, M.
Kliche, J.
Moliner Morro, A.
Mund, A.
Andersson, E.
McInerney, G.
Mann, M.
Jemth, P.
Davey, N.E.
Överby, A.K.
Nilsson, J.
Ivarsson, Y.
(2021). Large scale discovery of coronavirus-host factor protein interaction motifs reveals SARS-CoV-2 specific mechanisms and vulnerabilities. Nature communications,
Vol.12
(1).
show abstract
AbstractViral proteins make extensive use of short peptide interaction motifs to hijack cellular host factors. However, most current large-scale methods do not identify this important class of protein-protein interactions. Uncovering peptide mediated interactions provides both a molecular understanding of viral interactions with their host and the foundation for developing novel antiviral reagents. Here we describe a viral peptide discovery approach covering 23 coronavirus strains that provides high resolution information on direct virus-host interactions. We identify 269 peptide-based interactions for 18 coronaviruses including a specific interaction between the human G3BP1/2 proteins and an ΦxFG peptide motif in the SARS-CoV-2 nucleocapsid (N) protein. This interaction supports viral replication and through its ΦxFG motif N rewires the G3BP1/2 interactome to disrupt stress granules. A peptide-based inhibitor disrupting the G3BP1/2-N interaction dampened SARS-CoV-2 infection showing that our results can be directly translated into novel specific antiviral reagents..
Kumar, M.
Kumar, M.
Gouw, M.
Michael, S.
Sámano-Sánchez, H.
Pancsa, R.
Glavina, J.
Diakogianni, A.
Valverde, J.A.
Bukirova, D.
Čalyševa, J.
Palopoli, N.
Davey, N.E.
Chemes, L.B.
Gibson, T.J.
(2020). ELM-the eukaryotic linear motif resource in 2020. Nucleic acids research,
Vol.48
(D1),
pp. D296-D306.
show abstract
The eukaryotic linear motif (ELM) resource is a repository of manually curated experimentally validated short linear motifs (SLiMs). Since the initial release almost 20 years ago, ELM has become an indispensable resource for the molecular biology community for investigating functional regions in many proteins. In this update, we have added 21 novel motif classes, made major revisions to 12 motif classes and added >400 new instances mostly focused on DNA damage, the cytoskeleton, SH2-binding phosphotyrosine motifs and motif mimicry by pathogenic bacterial effector proteins. The current release of the ELM database contains 289 motif classes and 3523 individual protein motif instances manually curated from 3467 scientific publications. ELM is available at: http://elm.eu.org..
Palopoli, N.
Iserte, J.A.
Chemes, L.B.
Marino-Buslje, C.
Parisi, G.
Gibson, T.J.
Davey, N.E.
(2020). The articles ELM resource: simplifying access to protein linear motif literature by annotation, text-mining and classification. Database : the journal of biological databases and curation,
Vol.2020.
show abstract
Modern biology produces data at a staggering rate. Yet, much of these biological data is still isolated in the text, figures, tables and supplementary materials of articles. As a result, biological information created at great expense is significantly underutilised. The protein motif biology field does not have sufficient resources to curate the corpus of motif-related literature and, to date, only a fraction of the available articles have been curated. In this study, we develop a set of tools and a web resource, 'articles.ELM', to rapidly identify the motif literature articles pertinent to a researcher's interest. At the core of the resource is a manually curated set of about 8000 motif-related articles. These articles are automatically annotated with a range of relevant biological data allowing in-depth search functionality. Machine-learning article classification is used to group articles based on their similarity to manually curated motif classes in the Eukaryotic Linear Motif resource. Articles can also be manually classified within the resource. The 'articles.ELM' resource permits the rapid and accurate discovery of relevant motif articles thereby improving the visibility of motif literature and simplifying the recovery of valuable biological insights sequestered within scientific articles. Consequently, this web resource removes a critical bottleneck in scientific productivity for the motif biology field. Database URL: http://slim.icr.ac.uk/articles/..
Balasuriya, N.
Davey, N.E.
Johnson, J.L.
Liu, H.
Biggar, K.K.
Cantley, L.C.
Li, S.S.
O'Donoghue, P.
(2020). Phosphorylation-dependent substrate selectivity of protein kinase B (AKT1). Journal of biological chemistry,
Vol.295
(24),
pp. 8120-8134.
Wigington, C.P.
Roy, J.
Damle, N.P.
Yadav, V.K.
Blikstad, C.
Resch, E.
Wong, C.J.
Mackay, D.R.
Wang, J.T.
Krystkowiak, I.
Bradburn, D.A.
Tsekitsidou, E.
Hong, S.H.
Kaderali, M.A.
Xu, S.-.
Stearns, T.
Gingras, A.-.
Ullman, K.S.
Ivarsson, Y.
Davey, N.E.
Cyert, M.S.
(2020). Systematic Discovery of Short Linear Motifs Decodes Calcineurin Phosphatase Signaling. Molecular cell,
Vol.79
(2),
pp. 342-358.e12.
show abstract
Short linear motifs (SLiMs) drive dynamic protein-protein interactions essential for signaling, but sequence degeneracy and low binding affinities make them difficult to identify. We harnessed unbiased systematic approaches for SLiM discovery to elucidate the regulatory network of calcineurin (CN)/PP2B, the Ca 2+ -activated phosphatase that recognizes LxVP and PxIxIT motifs. In vitro proteome-wide detection of CN-binding peptides, in vivo SLiM-dependent proximity labeling, and in silico modeling of motif determinants uncovered unanticipated CN interactors, including NOTCH1, which we establish as a CN substrate. Unexpectedly, CN shows SLiM-dependent proximity to centrosomal and nuclear pore complex (NPC) proteins-structures where Ca 2+ signaling is largely uncharacterized. CN dephosphorylates human and yeast NPC proteins and promotes accumulation of a nuclear transport reporter, suggesting conserved NPC regulation by CN. The CN network assembled here provides a resource to investigate Ca 2+ and CN signaling and demonstrates synergy between experimental and computational methods, establishing a blueprint for examining SLiM-based networks..
Bandyopadhyay, S.
Bhaduri, S.
Örd, M.
Davey, N.E.
Loog, M.
Pryciak, P.M.
(2020). Comprehensive Analysis of G1 Cyclin Docking Motif Sequences that Control CDK Regulatory Potency In Vivo. Current biology : cb,
Vol.30
(22),
pp. 4454-4466.e5.
show abstract
Many protein-modifying enzymes recognize their substrates via docking motifs, but the range of functionally permissible motif sequences is often poorly defined. During eukaryotic cell division, cyclin-specific docking motifs help cyclin-dependent kinases (CDKs) phosphorylate different substrates at different stages, thus enforcing a temporally ordered series of events. In budding yeast, CDK substrates with Leu/Pro-rich (LP) docking motifs are recognized by Cln1/2 cyclins in late G1 phase, yet the key sequence features of these motifs were unknown. Here, we comprehensively analyze LP motif requirements in vivo by combining a competitive growth assay with deep mutational scanning. We quantified the effect of all single-residue replacements in five different LP motifs by using six distinct G1 cyclins from diverse fungi including medical and agricultural pathogens. The results uncover substantial tolerance for deviations from the consensus sequence, plus requirements at some positions that are contingent on the favorability of other motif residues. They also reveal the basis for variations in functional potency among wild-type motifs, and allow derivation of a quantitative matrix that predicts the strength of other candidate motif sequences. Finally, we find that variation in docking motif potency can advance or delay the time at which CDK substrate phosphorylation occurs, and thereby control the temporal ordering of cell cycle regulation. The overall results provide a general method for surveying viable docking motif sequences and quantifying their potency in vivo, and they reveal how variations in docking strength can tune the degree and timing of regulatory modifications..
Davey, N.E.
(2019). The functional importance of structure in unstructured protein regions. Current opinion in structural biology,
Vol.56,
pp. 155-163.
show abstract
After two decades of research, intrinsically disordered regions (IDRs) are established as a widespread phenomenon. The growing understanding of the significant functional role of IDRs has challenged the structure-function paradigm, proving irrefutably that a stably folded structure is not a strict requirement for function. Nonetheless, (un)structure-function relationships remain at the core of IDR-mediated interactions. An IDR can populate a continuously transitioning continuum of structural conformations from fully disordered to stable globular states. In these ensembles, only subsets of conformations are binding competent, with intramolecular IDR contacts serving as important intermolecular binding determinants. Here, we review our current understanding of different types of intramolecular IDR interactions, their effects on IDR complex formation and their modes of biological regulation..
Sebaa, R.
Johnson, J.
Pileggi, C.
Norgren, M.
Xuan, J.
Sai, Y.
Tong, Q.
Krystkowiak, I.
Bondy-Chorney, E.
Davey, N.E.
Krogan, N.
Downey, M.
Harper, M.-.
(2019). SIRT3 controls brown fat thermogenesis by deacetylation regulation of pathways upstream of UCP1. Molecular metabolism,
Vol.25,
pp. 35-49.
show abstract
Objective Brown adipose tissue (BAT) is important for thermoregulation in many mammals. Uncoupling protein 1 (UCP1) is the critical regulator of thermogenesis in BAT. Here we aimed to investigate the deacetylation control of BAT and to investigate a possible functional connection between UCP1 and sirtuin 3 (SIRT3), the master mitochondrial lysine deacetylase.Methods We carried out physiological, molecular, and proteomic analyses of BAT from wild-type and Sirt3KO mice when BAT is activated. Mice were either cold exposed for 2 days or were injected with the β3-adrenergic agonist, CL316,243 (1 mg/kg; i.p.). Mutagenesis studies were conducted in a cellular model to assess the impact of acetylation lysine sites on UCP1 function. Cardiac punctures were collected for proteomic analysis of blood acylcarnitines. Isolated mitochondria were used for functional analysis of OXPHOS proteins.Results Our findings showed that SIRT3 absence in mice resulted in impaired BAT lipid use, whole body thermoregulation, and respiration in BAT mitochondria, without affecting UCP1 expression. Acetylome profiling of BAT mitochondria revealed that SIRT3 regulates acetylation status of many BAT mitochondrial proteins including UCP1 and crucial upstream proteins. Mutagenesis work in cells suggested that UCP1 activity was independent of direct SIRT3-regulated lysine acetylation. However, SIRT3 impacted BAT mitochondrial proteins activities of acylcarnitine metabolism and specific electron transport chain complexes, CI and CII.Conclusions Our data highlight that SIRT3 likely controls BAT thermogenesis indirectly by targeting pathways upstream of UCP1..
Smith, R.J.
Cordeiro, M.H.
Davey, N.E.
Vallardi, G.
Ciliberto, A.
Gross, F.
Saurin, A.T.
(2019). PP1 and PP2A Use Opposite Phospho-dependencies to Control Distinct Processes at the Kinetochore. Cell reports,
Vol.28
(8),
pp. 2206-2219.e8.
show abstract
PP1 and PP2A-B56 are major serine/threonine phosphatase families that achieve specificity by colocalizing with substrates. At the kinetochore, however, both phosphatases localize to an almost identical molecular space and yet they still manage to regulate unique pathways and processes. By switching or modulating the positions of PP1/PP2A-B56 at kinetochores, we show that their unique downstream effects are not due to either the identity of the phosphatase or its precise location. Instead, these phosphatases signal differently because their kinetochore recruitment can be either inhibited (PP1) or enhanced (PP2A) by phosphorylation inputs. Mathematical modeling explains how these inverse phospho-dependencies elicit unique forms of cross-regulation and feedback, which allows otherwise indistinguishable phosphatases to produce distinct network behaviors and control different mitotic processes. Furthermore, our genome-wide analysis suggests that these major phosphatase families may have evolved to respond to phosphorylation inputs in opposite ways because many other PP1 and PP2A-B56-binding motifs are also phospho-regulated..
Jespersen, N.
Estelle, A.
Waugh, N.
Davey, N.E.
Blikstad, C.
Ammon, Y.-.
Akhmanova, A.
Ivarsson, Y.
Hendrix, D.A.
Barbar, E.
(2019). Systematic identification of recognition motifs for the hub protein LC8. Life science alliance,
Vol.2
(4),
pp. e201900366-e201900366.
show abstract
Hub proteins participate in cellular regulation by dynamic binding of multiple proteins within interaction networks. The hub protein LC8 reversibly interacts with more than 100 partners through a flexible pocket at its dimer interface. To explore the diversity of the LC8 partner pool, we screened for LC8 binding partners using a proteomic phage display library composed of peptides from the human proteome, which had no bias toward a known LC8 motif. Of the identified hits, we validated binding of 29 peptides using isothermal titration calorimetry. Of the 29 peptides, 19 were entirely novel, and all had the canonical TQT motif anchor. A striking observation is that numerous peptides containing the TQT anchor do not bind LC8, indicating that residues outside of the anchor facilitate LC8 interactions. Using both LC8-binding and nonbinding peptides containing the motif anchor, we developed the “LC8Pred” algorithm that identifies critical residues flanking the anchor and parses random sequences to predict LC8-binding motifs with ∼78% accuracy. Our findings significantly expand the scope of the LC8 hub interactome..
Ueki, Y.
Kruse, T.
Weisser, M.B.
Sundell, G.N.
Larsen, M.S.
Mendez, B.L.
Jenkins, N.P.
Garvanska, D.H.
Cressey, L.
Zhang, G.
Davey, N.
Montoya, G.
Ivarsson, Y.
Kettenbach, A.N.
Nilsson, J.
(2019). A Consensus Binding Motif for the PP4 Protein Phosphatase. Molecular cell,
Vol.76
(6),
pp. 953-964.e6.
Kruse, T.
Biedenkopf, N.
Hertz, E.P.
Dietzel, E.
Stalmann, G.
López-Méndez, B.
Davey, N.E.
Nilsson, J.
Becker, S.
(2018). The Ebola Virus Nucleoprotein Recruits the Host PP2A-B56 Phosphatase to Activate Transcriptional Support Activity of VP30. Molecular cell,
Vol.69
(1),
pp. 136-145.e6.
Krystkowiak, I.
Manguy, J.
Davey, N.E.
(2018). PSSMSearch: a server for modeling, visualization, proteome-wide discovery and annotation of protein motif specificity determinants. Nucleic acids research,
Vol.46
(W1),
pp. W235-W241.
Bentley-DeSousa, A.
Holinier, C.
Moteshareie, H.
Tseng, Y.-.
Kajjo, S.
Nwosu, C.
Amodeo, G.F.
Bondy-Chorney, E.
Sai, Y.
Rudner, A.
Golshani, A.
Davey, N.E.
Downey, M.
(2018). A Screen for Candidate Targets of Lysine Polyphosphorylation Uncovers a Conserved Network Implicated in Ribosome Biogenesis. Cell reports,
Vol.22
(13),
pp. 3427-3439.
Chhabra, S.
Fischer, P.
Takeuchi, K.
Dubey, A.
Ziarek, J.J.
Boeszoermenyi, A.
Mathieu, D.
Bermel, W.
Davey, N.E.
Wagner, G.
Arthanari, H.
(2018). 15
N detection harnesses the slow relaxation property of nitrogen: Delivering enhanced resolution for intrinsically disordered proteins. Proceedings of the national academy of sciences,
Vol.115
(8).
show abstract
Significance
Intrinsically disordered proteins (IDPs) have attracted significant attention due to their roles in crucial cellular processes. NMR is the only technique that allows the study of IDPs at atomic-level resolution. However, narrow chemical shift dispersion, rapid exchange with solvent, and high proline content challenge conventional
1
H-detected experiments. Here, we report the development of a suite of 3D experiments based on
15
N direct detection that harnesses the slow relaxation and the larger chemical shift dispersion of
15
N nuclei for complete backbone assignment of IDPs, including proline residues, which are critical to the study of IDPs. Using this approach, we have assigned the regulatory domain of NFATC2 and have identified a likely mechanism by which 14-3-3 proteins regulate NFAT nuclear translocation.
.
Gouw, M.
Michael, S.
Sámano-Sánchez, H.
Kumar, M.
Zeke, A.
Lang, B.
Bely, B.
Chemes, L.B.
Davey, N.E.
Deng, Z.
Diella, F.
Gürth, C.-.
Huber, A.-.
Kleinsorg, S.
Schlegel, L.S.
Palopoli, N.
Roey, K.V.
Altenberg, B.
Reményi, A.
Dinkel, H.
Gibson, T.J.
(2018). The eukaryotic linear motif resource - 2018 update. Nucleic acids res.,
Vol.46,
pp. D428-D434.
Piovesan, D.
Tabaro, F.
Paladin, L.
Necci, M.
Micetic, I.
Camilloni, C.
Davey, N.E.
Dosztányi, Z.
Mészáros, B.
Monzon, A.M.
Parisi, G.D.
Schád, É.
Sormanni, P.
Tompa, P.
Vendruscolo, M.
Vranken, W.F.
Tosatto, S.C.
(2018). MobiDB 3 0: more annotations for intrinsic disorder, conformational diversity and interactions in proteins. Nucleic acids res.,
Vol.46,
pp. D471-D476.
Davey, N.E.
Seo, M.
Yadav, V.K.
Jeon, J.
Nim, S.
Krystkowiak, I.
Blikstad, C.
Dong, D.
Markova, N.
Kim, P.M.
Ivarsson, Y.
(2017). Discovery of short linear motif‐mediated interactions through phage display of intrinsically disordered regions of the human proteome. The febs journal,
Vol.284
(3),
pp. 485-498.
Manguy, J.
Jehl, P.
Dillon, E.T.
Davey, N.E.
Shields, D.C.
Holton, T.A.
(2017). Peptigram: A Web-Based Application for Peptidomics Data Visualization. Journal of proteome research,
Vol.16
(2),
pp. 712-719.
Krystkowiak, I.
Davey, N.E.
(2017). SLiMSearch: a framework for proteome-wide discovery and annotation of functional modules in intrinsically disordered regions. Nucleic acids res.,
Vol.45,
pp. W464-W469.
Piovesan, D.
Tabaro, F.
Micetic, I.
Necci, M.
Quaglia, F.
Oldfield, C.J.
Aspromonte, M.C.
Davey, N.E.
Davidovic, R.
Dosztányi, Z.
Elofsson, A.
Gasparini, A.
Hatos, A.
Kajava, A.V.
Kalmár, L.
Leonardi, E.
Lazar, T.
Macedo-Ribeiro, S.
Macossay-Castillo, M.
Meszaros, A.
Minervini, G.
Murvai, N.
Pujols, J.
Roche, D.B.
Salladini, E.
Schád, É.
Schramm, A.
Szabó, B.
Tantos, Á.
Tonello, F.
Tsirigos, K.D.
Veljkovic, N.
Ventura, S.
Vranken, W.F.
Warholm, P.
Uversky, V.N.
Dunker, A.K.
Longhi, S.
Tompa, P.
Tosatto, S.C.
(2017). DisProt 7 0: a major update of the database of disordered proteins. Nucleic acids res.,
Vol.45,
pp. D219-D227.
Di Fiore, B.
Wurzenberger, C.
Davey, N.E.
Pines, J.
(2016). The Mitotic Checkpoint Complex Requires an Evolutionary Conserved Cassette to Bind and Inhibit Active APC/C. Molecular cell,
Vol.64
(6),
pp. 1144-1153.
show abstract
The Spindle Assembly Checkpoint (SAC) ensures genomic stability by preventing sister chromatid separation until all chromosomes are attached to the spindle. It catalyzes the production of the Mitotic Checkpoint Complex (MCC), which inhibits Cdc20 to inactivate the Anaphase Promoting Complex/Cyclosome (APC/C). Here we show that two Cdc20-binding motifs in BubR1 of the recently identified ABBA motif class are crucial for the MCC to recognize active APC/C-Cdc20. Mutating these motifs eliminates MCC binding to the APC/C, thereby abolishing the SAC and preventing cells from arresting in response to microtubule poisons. These ABBA motifs flank a KEN box to form a cassette that is highly conserved through evolution, both in the arrangement and spacing of the ABBA-KEN-ABBA motifs, and association with the amino-terminal KEN box required to form the MCC. We propose that the ABBA-KEN-ABBA cassette holds the MCC onto the APC/C by binding the two Cdc20 molecules in the MCC-APC/C complex..
Hertz, E.P.
Kruse, T.
Davey, N.E.
López-Méndez, B.
Sigurðsson, J.O.
Montoya, G.
Olsen, J.V.
Nilsson, J.
(2016). A Conserved Motif Provides Binding Specificity to the PP2A-B56 Phosphatase. Molecular cell,
Vol.63
(4),
pp. 686-695.
Davey, N.E.
Morgan, D.O.
(2016). Building a Regulatory Network with Short Linear Sequence Motifs: Lessons from the Degrons of the Anaphase-Promoting Complex. Molecular cell,
Vol.64
(1),
pp. 12-23.
Jehl, P.
Manguy, J.
Shields, D.C.
Higgins, D.G.
Davey, N.E.
(2016). ProViz - a web-based visualization tool to investigate the functional and evolutionary features of protein sequences. Nucleic acids res.,
Vol.44,
pp. W11-W15.
Dinkel, H.
Roey, K.V.
Michael, S.
Kumar, M.
Uyar, B.
Altenberg, B.
Milchevskaya, V.
Schneider, M.
Kühn, H.
Behrendt, A.
Dahl, S.L.
Damerell, V.
Diebel, S.
Kalman, S.
Klein, S.
Knudsen, A.C.
Mäder, C.
Merrill, S.
Staudt, A.
Thiel, V.
Welti, L.
Davey, N.E.
Diella, F.
Gibson, T.J.
(2016). ELM 2016 - data update and new functionality of the eukaryotic linear motif resource. Nucleic acids res.,
Vol.44,
pp. 294-300.
Downey, M.
Johnson, J.R.
Davey, N.E.
Newton, B.W.
Johnson, T.L.
Galaang, S.
Seller, C.A.
Krogan, N.
Toczyski, D.P.
(2015). Acetylome Profiling Reveals Overlap in the Regulation of Diverse Processes by Sirtuins, Gcn5, and Esa1. Molecular & cellular proteomics,
Vol.14
(1),
pp. 162-176.
Di Fiore, B.
Davey, N.E.
Hagting, A.
Izawa, D.
Mansfeld, J.
Gibson, T.J.
Pines, J.
(2015). The ABBA Motif Binds APC/C Activators and Is Shared by APC/C Substrates and Regulators. Developmental cell,
Vol.32
(3),
pp. 358-372.
Van Roey, K.
Davey, N.E.
(2015). Motif co-regulation and co-operativity are common mechanisms in transcriptional, post-transcriptional and post-translational regulation. Cell communication and signaling,
Vol.13
(1).
Davey, N.E.
Cyert, M.S.
Moses, A.M.
(2015). Short linear motifs – ex nihilo evolution of protein regulation. Cell communication and signaling,
Vol.13
(1).
Tompa, P.
Davey, N.E.
Gibson, T.J.
Babu, M.M.
(2014). A Million Peptide Motifs for the Molecular Biologist. Molecular cell,
Vol.55
(2),
pp. 161-169.
Van Roey, K.
Uyar, B.
Weatheritt, R.J.
Dinkel, H.
Seiler, M.
Budd, A.
Gibson, T.J.
Davey, N.E.
(2014). Short Linear Motifs: Ubiquitous and Functionally Diverse Protein Interaction Modules Directing Cell Regulation. Chemical reviews,
Vol.114
(13),
pp. 6733-6778.
Lu, D.
Hsiao, J.Y.
Davey, N.E.
Van Voorhis, V.A.
Foster, S.A.
Tang, C.
Morgan, D.O.
(2014). Multiple mechanisms determine the order of APC/C substrate degradation in mitosis. Journal of cell biology,
Vol.207
(1),
pp. 23-39.
show abstract
The ubiquitin protein ligase anaphase-promoting complex or cyclosome (APC/C) controls mitosis by promoting ordered degradation of securin, cyclins, and other proteins. The mechanisms underlying the timing of APC/C substrate degradation are poorly understood. We explored these mechanisms using quantitative fluorescence microscopy of GFP-tagged APC/CCdc20 substrates in living budding yeast cells. Degradation of the S cyclin, Clb5, begins early in mitosis, followed 6 min later by the degradation of securin and Dbf4. Anaphase begins when less than half of securin is degraded. The spindle assembly checkpoint delays the onset of Clb5 degradation but does not influence securin degradation. Early Clb5 degradation depends on its interaction with the Cdk1–Cks1 complex and the presence of a Cdc20-binding “ABBA motif” in its N-terminal region. The degradation of securin and Dbf4 is delayed by Cdk1-dependent phosphorylation near their Cdc20-binding sites. Thus, a remarkably diverse array of mechanisms generates robust ordering of APC/CCdc20 substrate destruction..
Davey, N.E.
Satagopam, V.P.
Santiago-Mozos, S.
Villacorta-Martin, C.
Bharat, T.A.
Schneider, R.
Briggs, J.A.
(2014). The HIV Mutation Browser: A Resource for Human Immunodeficiency Virus Mutagenesis and Polymorphism Data. Plos comput. biol.,
Vol.10.
Dinkel, H.
Roey, K.V.
Michael, S.
Davey, N.E.
Weatheritt, R.J.
Born, D.
Speck, T.
Krüger, D.
Grebnev, G.
Kuban, M.
Strumillo, M.
Uyar, B.
Budd, A.
Altenberg, B.
Seiler, M.
Chemes, L.B.
Glavina, J.
Sánchez, I.E.
Diella, F.
Gibson, T.J.
(2014). The eukaryotic linear motif resource ELM: 10 years and counting. Nucleic acids res.,
Vol.42,
pp. 259-266.
Perfetto, L.
Gherardini, P.F.
Davey, N.E.
Diella, F.
Helmer-Citterich, M.
Cesareni, G.
(2013). Exploring the diversity of SPRY/B30 2-mediated interactions. Trends in biochemical sciences,
Vol.38
(1),
pp. 38-46.
Van Roey, K.
Dinkel, H.
Weatheritt, R.J.
Gibson, T.J.
Davey, N.E.
(2013). The switches ELM Resource: A Compendium of Conditional Regulatory Interaction Interfaces. Science signaling,
Vol.6
(269).
show abstract
A resource centered on short linear motifs provides a repository and exploratory tool for conditional protein interactions..
Castello, A.
Fischer, B.
Eichelbaum, K.
Horos, R.
Beckmann, B.M.
Strein, C.
Davey, N.E.
Humphreys, D.T.
Preiss, T.
Steinmetz, L.M.
Krijgsveld, J.
Hentze, M.W.
(2012). Insights into RNA Biology from an Atlas of Mammalian mRNA-Binding Proteins. Cell,
Vol.149
(6),
pp. 1393-1406.
Van Roey, K.
Gibson, T.J.
Davey, N.E.
(2012). Motif switches: decision-making in cell regulation. Current opinion in structural biology,
Vol.22
(3),
pp. 378-385.
Vijayakumar, V.
Guerrero, A.N.
Davey, N.
Lebrilla, C.B.
Shields, D.C.
Khaldi, N.
(2012). EnzymePredictor: A Tool for Predicting and Visualizing Enzymatic Cleavages of Digested Proteins. Journal of proteome research,
Vol.11
(12),
pp. 6056-6065.
Weatheritt, R.J.
Davey, N.E.
Gibson, T.J.
(2012). Linear motifs confer functional diversity onto splice variants. Nucleic acids research,
Vol.40
(15),
pp. 7123-7131.
Jiang, K.
Toedt, G.
Montenegro Gouveia, S.
Davey, N.E.
Hua, S.
van der Vaart, B.
Grigoriev, I.
Larsen, J.
Pedersen, L.B.
Bezstarosti, K.
Lince-Faria, M.
Demmers, J.
Steinmetz, M.O.
Gibson, T.J.
Akhmanova, A.
(2012). A Proteome-wide Screen for Mammalian SxIP Motif-Containing Microtubule Plus-End Tracking Proteins. Current biology,
Vol.22
(19),
pp. 1800-1807.
Davey, N.E.
Cowan, J.L.
Shields, D.C.
Gibson, T.J.
Coldwell, M.J.
Edwards, R.J.
(2012). SLiMPrints: conservation-based discovery of functional motif fingerprints in intrinsically disordered protein regions. Nucleic acids research,
Vol.40
(21),
pp. 10628-10641.
Naumer, M.
Sonntag, F.
Schmidt, K.
Nieto, K.
Panke, C.
Davey, N.E.
Popa-Wagner, R.
Kleinschmidt, J.A.
(2012). Properties of the Adeno-Associated Virus Assembly-Activating Protein. Journal of virology,
Vol.86
(23),
pp. 13038-13048.
show abstract
ABSTRACT
Adeno-associated virus (AAV) capsid assembly requires expression of the assembly-activating protein (AAP) together with capsid proteins VP1, VP2, and VP3. AAP is encoded by an alternative open reading frame of the
cap
gene. Sequence analysis and site-directed mutagenesis revealed that AAP contains two hydrophobic domains in the N-terminal part of the molecule that are essential for its assembly-promoting activity. Mutation of these sequences reduced the interaction of AAP with the capsid proteins. Deletions and a point mutation in the capsid protein C terminus also abolished capsid assembly and strongly reduced the interaction with AAP. Interpretation of these observations on a structural basis suggests an interaction of AAP with the VP C terminus, which forms the capsid protein interface at the 2-fold symmetry axis. This interpretation is supported by a decrease in the interaction of monoclonal antibody B1 with VP3 under nondenaturing conditions in the presence of AAP, indicative of steric hindrance of B1 binding to its C-terminal epitope by AAP. In addition, AAP forms high-molecular-weight oligomers and changes the conformation of nonassembled VP molecules as detected by conformation-sensitive monoclonal antibodies A20 and C37. Combined, these observations suggest a possible scaffolding activity of AAP in the AAV capsid assembly reaction.
.
Bharat, T.A.
Davey, N.E.
Ulbrich, P.
Riches, J.D.
de Marco, A.
Rumlova, M.
Sachse, C.
Ruml, T.
Briggs, J.A.
(2012). Structure of the immature retroviral capsid at 8 Å resolution by cryo-electron microscopy. Nature,
Vol.487
(7407),
pp. 385-389.
Weatheritt, R.J.
Luck, K.
Petsalaki, E.
Davey, N.E.
Gibson, T.J.
(2012). The identification of short linear motif-mediated interfaces within the human interactome. Bioinform.,
Vol.28,
pp. 976-982.
Dinkel, H.
Michael, S.
Weatheritt, R.J.
Davey, N.E.
Roey, K.V.
Altenberg, B.
Toedt, G.
Uyar, B.
Seiler, M.
Budd, A.
Jödicke, L.
Dammert, M.A.
Schroeter, C.
Hammer, M.
Schmidt, T.
Jehl, P.
McGuigan, C.
Dymecka, M.
Chica, C.
Luck, K.
Via, A.
Chatr-aryamontri, A.
Haslam, N.J.
Grebnev, G.
Edwards, R.J.
Steinmetz, M.O.
Meiselbach, H.
Diella, F.
Gibson, T.J.
(2012). ELM - the database of eukaryotic linear motifs. Nucleic acids res.,
Vol.40,
pp. 242-251.
Davey, N.E.
Travé, G.
Gibson, T.J.
(2011). How viruses hijack cell regulation. Trends in biochemical sciences,
Vol.36
(3),
pp. 159-169.
Davey, N.E.
Haslam, N.J.
Shields, D.C.
Edwards, R.J.
(2011). SLiMSearch 2 0: biological context for short linear motifs in proteins. Nucleic acids res.,
Vol.39,
pp. 56-60.
Mooney, C.
Davey, N.
Martin, A.J.
Walsh, I.
Shields, D.C.
Pollastri, G.
(2011). In Silico Protein Motif Discovery and Structural Analysis. ,
,
pp. 341-353.
Gould, C.M.
Diella, F.
Via, A.
Puntervoll, P.
Gemünd, C.
Chabanis-Davidson, S.
Michael, S.
Sayadi, A.
Bryne, J.C.
Chica, C.
Seiler, M.
Davey, N.E.
Haslam, N.
Weatheritt, R.J.
Budd, A.
Hughes, T.
Pas, J.
Rychlewski, L.
Travé, G.
Aasland, R.
Helmer-Citterich, M.
Linding, R.
Gibson, T.J.
(2010). ELM: the status of the 2010 eukaryotic linear motif resource. Nucleic acids res,
Vol.38
(Database issue),
pp. D167-D180.
show abstract
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..
de Marco, A.
Davey, N.E.
Ulbrich, P.
Phillips, J.M.
Lux, V.
Riches, J.D.
Fuzik, T.
Ruml, T.
Kräusslich, H.-.
Vogt, V.M.
Briggs, J.A.
(2010). Conserved and Variable Features of Gag Structure and Arrangement in Immature Retrovirus Particles. Journal of virology,
Vol.84
(22),
pp. 11729-11736.
show abstract
ABSTRACT
The assembly of retroviruses is driven by oligomerization of the Gag polyprotein. We have used cryo-electron tomography together with subtomogram averaging to describe the three-dimensional structure of
in vitro
-assembled Gag particles from human immunodeficiency virus, Mason-Pfizer monkey virus, and Rous sarcoma virus. These represent three different retroviral genera: the lentiviruses, betaretroviruses and alpharetroviruses. Comparison of the three structures reveals the features of the supramolecular organization of Gag that are conserved between genera and therefore reflect general principles of Gag-Gag interactions and the features that are specific to certain genera. All three Gag proteins assemble to form approximately spherical hexameric lattices with irregular defects. In all three genera, the N-terminal domain of CA is arranged in hexameric rings around large holes. Where the rings meet, 2-fold densities, assigned to the C-terminal domain of CA, extend between adjacent rings, and link together at the 6-fold symmetry axis with a density, which extends toward the center of the particle into the nucleic acid layer. Although this general arrangement is conserved, differences can be seen throughout the CA and spacer peptide regions. These differences can be related to sequence differences among the genera. We conclude that the arrangement of the structural domains of CA is well conserved across genera, whereas the relationship between CA, the spacer peptide region, and the nucleic acid is more specific to each genus.
.
Davey, N.E.
Edwards, R.J.
Shields, D.C.
(2010). Estimation and efficient computation of the true probability of recurrence of short linear protein sequence motifs in unrelated proteins. Bmc bioinform.,
Vol.11,
pp. 14-14.
Davey, N.E.
Haslam, N.J.
Shields, D.C.
Edwards, R.J.
(2010). SLiMFinder: a web server to find novel, significantly over-represented, short protein motifs. Nucleic acids res.,
Vol.38,
pp. 534-539.
Davey, N.E.
(2010). Computational identification and analysis of protein short linear motifs. Frontiers in bioscience,
Vol.15
(1),
pp. 801-801.
Davey, N.E.
Shields, D.C.
Edwards, R.J.
(2009). Masking residues using context-specific evolutionary conservation significantly improves short linear motif discovery. Bioinform.,
Vol.25,
pp. 443-450.
Casey, F.P.
Davey, N.E.
Baran, I.
Vareková, R.S.
Shields, D.C.
(2008). Web Server To Identify Similarity of Amino Acid Motifs to Compounds (SAAMCO). J. chem. inf. model.,
Vol.48,
pp. 1524-1529.
Edwards, R.J.
Davey, N.E.
Shields, D.C.
(2008). CompariMotif: quick and easy comparisons of sequence motifs. Bioinform.,
Vol.24,
pp. 1307-1309.
Davey, N.E.
Edwards, R.J.
Shields, D.C.
(2007). The SLiMDisc server: short, linear motif discovery in proteins. Nucleic acids res.,
Vol.35,
pp. 455-459.
Davey, N.E.
(2006). SLiMDisc: short, linear motif discovery, correcting for common evolutionary descent. Nucleic acids research,
Vol.34
(12),
pp. 3546-3554.
Parthasarathi, L.
Devocelle, M.
Søndergaard, C.R.
Baran, I.
O'Dushlaine, C.
Davey, N.E.
Edwards, R.J.
Moran, N.
Kenny, D.
Shields, D.C.
(2006). Absolute Net Charge and the Biological Activity of Oligopeptides. J. chem. inf. model.,
Vol.46,
pp. 2183-2190.
Davey, N.E.
Van Roey, K.
Weatheritt, R.J.
Toedt, G.
Uyar, B.
Altenberg, B.
Budd, A.
Diella, F.
Dinkel, H.
Gibson, T.J.
Attributes of short linear motifs. Mol. biosyst.,
Vol.8
(1),
pp. 268-281.
Uyar, B.
Weatheritt, R.J.
Dinkel, H.
Davey, N.E.
Gibson, T.J.
Proteome-wide analysis of human disease mutations in short linear motifs: neglected players in cancer?. Mol. biosyst.,
Vol.10
(10),
pp. 2626-2642.
show abstract
Mutations in short linear motifs impair the functions of intrinsically disordered proteins in cellular signaling/regulation and contribute substantially to human diseases.
.
Pushker, R.
Mooney, C.
Davey, N.E.
Jacqué, J.-.
Shields, D.C.
Marked Variability in the Extent of Protein Disorder within and between Viral Families. Plos one,
Vol.8
(4),
pp. e60724-e60724.
Edwards, R.J.
Davey, N.E.
Brien, K.O.
Shields, D.C.
Interactome-wide prediction of short, disordered protein interaction motifs in humans. Mol. biosyst.,
Vol.8
(1),
pp. 282-295.
Stavropoulos, I.
Khaldi, N.
Davey, N.E.
O’Brien, K.
Martin, F.
Shields, D.C.
Protein Disorder and Short Conserved Motifs in Disordered Regions Are Enriched near the Cytoplasmic Side of Single-Pass Transmembrane Proteins. Plos one,
Vol.7
(9),
pp. e44389-e44389.
Bharat, T.A.
Riches, J.D.
Kolesnikova, L.
Welsch, S.
Krähling, V.
Davey, N.
Parsy, M.-.
Becker, S.
Briggs, J.A.
Cryo-Electron Tomography of Marburg Virus Particles and Their Morphogenesis within Infected Cells. Plos biology,
Vol.9
(11),
pp. e1001196-e1001196.
Edwards, R.J.
Davey, N.E.
Shields, D.C.
SLiMFinder: A Probabilistic Method for Identifying Over-Represented, Convergently Evolved, Short Linear Motifs in Proteins. Plos one,
Vol.2
(10),
pp. e967-e967.
Hatos, A.
Hajdu-Soltész, B.
Monzon, A.M.
Palopoli, N.
Álvarez, L.
Aykac-Fas, B.
Bassot, C.
Benítez, G.I.
Bevilacqua, M.
Chasapi, A.
Chemes, L.
Davey, N.E.
Davidović, R.
Dunker, A.K.
Elofsson, A.
Gobeill, J.
Foutel, N.S.
Sudha, G.
Guharoy, M.
Horvath, T.
Iglesias, V.
Kajava, A.V.
Kovacs, O.P.
Lamb, J.
Lambrughi, M.
Lazar, T.
Leclercq, J.Y.
Leonardi, E.
Macedo-Ribeiro, S.
Macossay-Castillo, M.
Maiani, E.
Manso, J.A.
Marino-Buslje, C.
Martínez-Pérez, E.
Mészáros, B.
Mičetić, I.
Minervini, G.
Murvai, N.
Necci, M.
Ouzounis, C.A.
Pajkos, M.
Paladin, L.
Pancsa, R.
Papaleo, E.
Parisi, G.
Pasche, E.
Barbosa Pereira, P.J.
Promponas, V.J.
Pujols, J.
Quaglia, F.
Ruch, P.
Salvatore, M.
Schad, E.
Szabo, B.
Szaniszló, T.
Tamana, S.
Tantos, A.
Veljkovic, N.
Ventura, S.
Vranken, W.
Dosztányi, Z.
Tompa, P.
Tosatto, S.C.
Piovesan, D.
DisProt: intrinsic protein disorder annotation in 2020. Nucleic acids research,
.
show abstract
Abstract The Database of Protein Disorder (DisProt, URL: https://disprot.org) provides manually curated annotations of intrinsically disordered proteins from the literature. Here we report recent developments with DisProt (version 8), including the doubling of protein entries, a new disorder ontology, improvements of the annotation format and a completely new website. The website includes a redesigned graphical interface, a better search engine, a clearer API for programmatic access and a new annotation interface that integrates text mining technologies. The new entry format provides a greater flexibility, simplifies maintenance and allows the capture of more information from the literature. The new disorder ontology has been formalized and made interoperable by adopting the OWL format, as well as its structure and term definitions have been improved. The new annotation interface has made the curation process faster and more effective. We recently showed that new DisProt annotations can be effectively used to train and validate disorder predictors. We believe the growth of DisProt will accelerate, contributing to the improvement of function and disorder predictors and therefore to illuminate the ‘dark’ proteome..
Piovesan, D.
Necci, M.
Escobedo, N.
Monzon, A.M.
Hatos, A.
Mičetić, I.
Quaglia, F.
Paladin, L.
Ramasamy, P.
Dosztányi, Z.
Vranken, W.F.
Davey, N.E.
Parisi, G.
Fuxreiter, M.
Tosatto, S.C.
MobiDB: intrinsically disordered proteins in 2021. Nucleic acids research,
Vol.49
(D1),
pp. D361-D367.
show abstract
The MobiDB database (URL: https://mobidb.org/) provides predictions and annotations for intrinsically disordered proteins. Here, we report recent developments implemented in MobiDB version 4, regarding the database format, with novel types of annotations and an improved update process. The new website includes a re-designed user interface, a more effective search engine and advanced API for programmatic access. The new database schema gives more flexibility for the users, as well as simplifying the maintenance and updates. In addition, the new entry page provides more visualisation tools including customizable feature viewer and graphs of the residue contact maps. MobiDB v4 annotates the binding modes of disordered proteins, whether they undergo disorder-to-order transitions or remain disordered in the bound state. In addition, disordered regions undergoing liquid-liquid phase separation or post-translational modifications are defined. The integrated information is presented in a simplified interface, which enables faster searches and allows large customized datasets to be downloaded in TSV, Fasta or JSON formats. An alternative advanced interface allows users to drill deeper into features of interest. A new statistics page provides information at database and proteome levels. The new MobiDB version presents state-of-the-art knowledge on disordered proteins and improves data accessibility for both computational and experimental users..
Quaglia, F.
Mészáros, B.
Salladini, E.
Hatos, A.
Pancsa, R.
Chemes, L.B.
Pajkos, M.
Lazar, T.
Peña-Díaz, S.
Santos, J.
Ács, V.
Farahi, N.
Fichó, E.
Aspromonte, M.C.
Bassot, C.
Chasapi, A.
Davey, N.E.
Davidović, R.
Dobson, L.
Elofsson, A.
Erdős, G.
Gaudet, P.
Giglio, M.
Glavina, J.
Iserte, J.
Iglesias, V.
Kálmán, Z.
Lambrughi, M.
Leonardi, E.
Longhi, S.
Macedo-Ribeiro, S.
Maiani, E.
Marchetti, J.
Marino-Buslje, C.
Mészáros, A.
Monzon, A.M.
Minervini, G.
Nadendla, S.
Nilsson, J.F.
Novotný, M.
Ouzounis, C.A.
Palopoli, N.
Papaleo, E.
Pereira, P.J.
Pozzati, G.
Promponas, V.J.
Pujols, J.
Rocha, A.C.
Salas, M.
Sawicki, L.R.
Schad, E.
Shenoy, A.
Szaniszló, T.
Tsirigos, K.D.
Veljkovic, N.
Parisi, G.
Ventura, S.
Dosztányi, Z.
Tompa, P.
Tosatto, S.C.
Piovesan, D.
DisProt in 2022: improved quality and accessibility of protein intrinsic disorder annotation. Nucleic acids research,
Vol.50
(D1),
pp. D480-D487.
show abstract
The Database of Intrinsically Disordered Proteins (DisProt, URL: https://disprot.org) is the major repository of manually curated annotations of intrinsically disordered proteins and regions from the literature. We report here recent updates of DisProt version 9, including a restyled web interface, refactored Intrinsically Disordered Proteins Ontology (IDPO), improvements in the curation process and significant content growth of around 30%. Higher quality and consistency of annotations is provided by a newly implemented reviewing process and training of curators. The increased curation capacity is fostered by the integration of DisProt with APICURON, a dedicated resource for the proper attribution and recognition of biocuration efforts. Better interoperability is provided through the adoption of the Minimum Information About Disorder (MIADE) standard, an active collaboration with the Gene Ontology (GO) and Evidence and Conclusion Ontology (ECO) consortia and the support of the ELIXIR infrastructure..
Kumar, M.
Michael, S.
Alvarado-Valverde, J.
Mészáros, B.
Sámano-Sánchez, H.
Zeke, A.
Dobson, L.
Lazar, T.
Örd, M.
Nagpal, A.
Farahi, N.
Käser, M.
Kraleti, R.
Davey, N.E.
Pancsa, R.
Chemes, L.B.
Gibson, T.J.
The Eukaryotic Linear Motif resource: 2022 release. Nucleic acids research,
Vol.50
(D1),
pp. D497-D508.
show abstract
Almost twenty years after its initial release, the Eukaryotic Linear Motif (ELM) resource remains an invaluable source of information for the study of motif-mediated protein-protein interactions. ELM provides a comprehensive, regularly updated and well-organised repository of manually curated, experimentally validated short linear motifs (SLiMs). An increasing number of SLiM-mediated interactions are discovered each year and keeping the resource up-to-date continues to be a great challenge. In the current update, 30 novel motif classes have been added and five existing classes have undergone major revisions. The update includes 411 new motif instances mostly focused on cell-cycle regulation, control of the actin cytoskeleton, membrane remodelling and vesicle trafficking pathways, liquid-liquid phase separation and integrin signalling. Many of the newly annotated motif-mediated interactions are targets of pathogenic motif mimicry by viral, bacterial or eukaryotic pathogens, providing invaluable insights into the molecular mechanisms underlying infectious diseases. The current ELM release includes 317 motif classes incorporating 3934 individual motif instances manually curated from 3867 scientific publications. ELM is available at: http://elm.eu.org..
Benz, C.
Ali, M.
Krystkowiak, I.
Simonetti, L.
Sayadi, A.
Mihalic, F.
Kliche, J.
Andersson, E.
Jemth, P.
Davey, N.E.
Ivarsson, Y.
Proteome-scale mapping of binding sites in the unstructured regions of the human proteome. Molecular systems biology,
Vol.18
(1),
pp. e10584-?.
show abstract
Specific protein-protein interactions are central to all processes that underlie cell physiology. Numerous studies have together identified hundreds of thousands of human protein-protein interactions. However, many interactions remain to be discovered, and low affinity, conditional, and cell type-specific interactions are likely to be disproportionately underrepresented. Here, we describe an optimized proteomic peptide-phage display library that tiles all disordered regions of the human proteome and allows the screening of ~ 1,000,000 overlapping peptides in a single binding assay. We define guidelines for processing, filtering, and ranking the results and provide PepTools, a toolkit to annotate the identified hits. We uncovered >2,000 interaction pairs for 35 known short linear motif (SLiM)-binding domains and confirmed the quality of the produced data by complementary biophysical or cell-based assays. Finally, we show how the amino acid resolution-binding site information can be used to pinpoint functionally important disease mutations and phosphorylation events in intrinsically disordered regions of the proteome. The optimized human disorderome library paired with PepTools represents a powerful pipeline for unbiased proteome-wide discovery of SLiM-based interactions..
Ripamonti, M.
Lamarca, A.
Davey, N.E.
Tonoli, D.
Surini, S.
de Curtis, I.
A functional interaction between liprin-α1 and B56γ regulatory subunit of protein phosphatase 2A supports tumor cell motility. Communications biology,
Vol.5
(1).
show abstract
AbstractScaffold liprin-α1 is required to assemble dynamic plasma membrane-associated platforms (PMAPs) at the front of migrating breast cancer cells, to promote protrusion and invasion. We show that the N-terminal region of liprin-α1 contains an LxxIxE motif interacting with B56 regulatory subunits of serine/threonine protein phosphatase 2A (PP2A). The specific interaction of B56γ with liprin-α1 requires an intact motif, since two point mutations strongly reduce the interaction. B56γ mediates the interaction of liprin-α1 with the heterotrimeric PP2A holoenzyme. Most B56γ protein is recovered in the cytosolic fraction of invasive MDA-MB-231 breast cancer cells, where B56γ is complexed with liprin-α1. While mutation of the short linear motif (SLiM) does not affect localization of liprin-α1 to PMAPs, localization of B56γ at these sites specifically requires liprin-α1. Silencing of B56γ or liprin-α1 inhibits to similar extent cell spreading on extracellular matrix, invasion, motility and lamellipodia dynamics in migrating MDA-MB-231 cells, suggesting that B56γ/PP2A is a novel component of the PMAPs machinery regulating tumor cell motility. In this direction, inhibition of cell spreading by silencing liprin-α1 is not rescued by expression of B56γ binding-defective liprin-α1 mutant. We propose that liprin-α1-mediated recruitment of PP2A via B56γ regulates cell motility by controlling protrusion in migrating MDA-MB-231 cells..