JASSA: a comprehensive tool for prediction of SUMOylation sites and SIMs

MOTIVATION Post-translational modification by the Small Ubiquitin-like Modifier (SUMO) proteins, a process termed SUMOylation, is involved in many fundamental cellular processes. SUMO proteins are conjugated to a protein substrate, creating an interface for the recruitment of cofactors harboring SUMO-interacting motifs (SIMs). Mapping both SUMO-conjugation sites and SIMs is required to study the functional consequence of SUMOylation. To define the best candidate sites for experimental validation we designed JASSA, a Joint Analyzer of SUMOylation site and SIMs. RESULTS JASSA is a predictor that uses a scoring system based on a Position Frequency Matrix derived from the alignment of experimental SUMOylation sites or SIMs. Compared with existing web-tools, JASSA displays on par or better performances. Novel features were implemented towards a better evaluation of the prediction, including identification of database hits matching the query sequence and representation of candidate sites within the secondary structural elements and/or the 3D fold of the protein of interest, retrievable from deposited PDB files. AVAILABILITY AND IMPLEMENTATION JASSA is freely accessible at http://www.jassa.fr/. Website is implemented in PHP and MySQL, with all major browsers supported. CONTACT guillaume.beauclair@inserm.fr SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.

[1]  N. Picard,et al.  Identification of Estrogen Receptor β as a SUMO-1 Target Reveals a Novel Phosphorylated Sumoylation Motif and Regulation by Glycogen Synthase Kinase 3β , 2012, Molecular and Cellular Biology.

[2]  I. Matic,et al.  Proteome-Wide Identification of SUMO2 Modification Sites , 2014, Science Signaling.

[3]  R. Hay,et al.  SUMO-1 Conjugation in Vivo Requires Both a Consensus Modification Motif and Nuclear Targeting* , 2001, The Journal of Biological Chemistry.

[4]  C. Lima,et al.  A molecular basis for phosphorylation-dependent SUMO conjugation by the E2 Ubc9 , 2009, Nature Structural &Molecular Biology.

[5]  I. Dikic,et al.  Specification of SUMO 1-and SUMO 2-interacting Motifs * , 2006 .

[6]  T. Hunter,et al.  Poly-Small Ubiquitin-like Modifier (PolySUMO)-binding Proteins Identified through a String Search* , 2012, The Journal of Biological Chemistry.

[7]  Hadley Wickham,et al.  ggplot2 - Elegant Graphics for Data Analysis (2nd Edition) , 2017 .

[8]  A. Dejean,et al.  An Acetylation/Deacetylation-SUMOylation Switch through a Phylogenetically Conserved ψKXEP Motif in the Tumor Suppressor HIC1 Regulates Transcriptional Repression Activity , 2007, Molecular and Cellular Biology.

[9]  Min Wang,et al.  The Small Ubiquitin-like Modifier-1 (SUMO-1) Consensus Sequence Mediates Ubc9 Binding and Is Essential for SUMO-1 Modification* , 2001, The Journal of Biological Chemistry.

[10]  J. Martens,et al.  SUMO modification regulates inactivation of the voltage-gated potassium channel Kv1.5 , 2007, Proceedings of the National Academy of Sciences.

[11]  Xavier Robin,et al.  pROC: an open-source package for R and S+ to analyze and compare ROC curves , 2011, BMC Bioinformatics.

[12]  J. Theriot,et al.  Mu gets in the loop. , 2010, Molecular cell.

[13]  M. Kaghad,et al.  Covalent modification of p73alpha by SUMO-1. Two-hybrid screening with p73 identifies novel SUMO-1-interacting proteins and a SUMO-1 interaction motif. , 2000, The Journal of biological chemistry.

[14]  L. Mikkonen,et al.  SUMO-1 conjugation in normal and stress conditions in vivo , 2013 .

[15]  Chiou-Hong Lin,et al.  Structural and functional roles of Daxx SIM phosphorylation in SUMO paralog-selective binding and apoptosis modulation. , 2011, Molecular cell.

[16]  F. Melchior,et al.  Sumoylation: a regulatory protein modification in health and disease. , 2013, Annual review of biochemistry.

[17]  Yan Xuan,et al.  Direct binding of CoREST1 to SUMO-2/3 contributes to gene-specific repression by the LSD1/CoREST1/HDAC complex. , 2009, Molecular cell.

[18]  Roman Körner,et al.  SUMO modification of the ubiquitin-conjugating enzyme E2-25K , 2005, Nature Structural &Molecular Biology.

[19]  A. Sharrocks,et al.  An extended consensus motif enhances the specificity of substrate modification by SUMO , 2006, The EMBO journal.

[20]  Zhen Chen,et al.  SUMOhydro: A Novel Method for the Prediction of Sumoylation Sites Based on Hydrophobic Properties , 2012, PloS one.

[21]  K. Sarge,et al.  Sumoylation and human disease pathogenesis. , 2009, Trends in biochemical sciences.

[22]  M. Mann,et al.  Comparative Proteomic Analysis Identifies a Role for SUMO in Protein Quality Control , 2011, Science Signaling.

[23]  Sampsa Hautaniemi,et al.  Novel Proteomics Strategy Brings Insight into the Prevalence of SUMO-2 Target Sites* , 2009, Molecular & Cellular Proteomics.

[24]  T. Ikegami,et al.  Structure of the Small Ubiquitin-like Modifier (SUMO)-interacting Motif of MBD1-containing Chromatin-associated Factor 1 Bound to SUMO-3* , 2008, Journal of Biological Chemistry.

[25]  G. Crooks,et al.  WebLogo: a sequence logo generator. , 2004, Genome research.

[26]  M. Mann,et al.  Uncovering Global SUMOylation Signaling Networks in a Site-Specific Manner , 2014, Nature Structural &Molecular Biology.

[27]  Ziming Zhang,et al.  Small Ubiquitin-like Modifier (SUMO) Recognition of a SUMO Binding Motif , 2005, Journal of Biological Chemistry.

[28]  Jaclyn R. Gareau,et al.  The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition , 2010, Nature Reviews Molecular Cell Biology.

[29]  L. Sistonen,et al.  PDSM, a motif for phosphorylation-dependent SUMO modification. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[30]  K. Hofmann,et al.  Sumoylation as a signal for polyubiquitylation and proteasomal degradation. , 2010, Sub-cellular biochemistry.

[31]  Florian Gnad,et al.  Site-specific identification of SUMO-2 targets in cells reveals an inverted SUMOylation motif and a hydrophobic cluster SUMOylation motif. , 2010, Molecular cell.

[32]  F. Melchior,et al.  SUMO--nonclassical ubiquitin. , 2000, Annual review of cell and developmental biology.

[33]  A. Pichler,et al.  SUMO Rules: Regulatory Concepts and Their Implication in Neurologic Functions , 2013, NeuroMolecular Medicine.

[34]  T. Dobner,et al.  Human Pathogens and the Host Cell SUMOylation System , 2011, Journal of Virology.

[35]  Ming-Ming Zhou,et al.  PHD domain-mediated E3 ligase activity directs intramolecular sumoylation of an adjacent bromodomain required for gene silencing. , 2007, Molecular cell.

[36]  V. Wilson Sumoylation at the Host-Pathogen Interface , 2012, Biomolecules.

[37]  P. Cossart,et al.  Mapping of SUMO sites and analysis of SUMOylation changes induced by external stimuli , 2014, Proceedings of the National Academy of Sciences.

[38]  Yu Xue,et al.  Systematic study of protein sumoylation: Development of a site‐specific predictor of SUMOsp 2.0 , 2009, Proteomics.

[39]  Qi Zhao,et al.  GPS-SUMO: a tool for the prediction of sumoylation sites and SUMO-interaction motifs , 2014, Nucleic Acids Res..

[40]  Andrew Emili,et al.  Defining the SUMO-modified Proteome by Multiple Approaches in Saccharomyces cerevisiae* , 2005, Journal of Biological Chemistry.

[41]  Ivan Dikic,et al.  Specification of SUMO1- and SUMO2-interacting Motifs* , 2006, Journal of Biological Chemistry.

[42]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[43]  J. Iñiguez-Lluhí,et al.  A Synergy Control Motif within the Attenuator Domain of CCAAT/Enhancer-binding Protein α Inhibits Transcriptional Synergy through Its PIASy-enhanced Modification by SUMO-1 or SUMO-3* , 2003, The Journal of Biological Chemistry.

[44]  Cathy H. Wu,et al.  UniProt: the Universal Protein knowledgebase , 2004, Nucleic Acids Res..

[45]  Erik Meulmeester,et al.  Mechanism and consequences for paralog-specific sumoylation of ubiquitin-specific protease 25. , 2008, Molecular cell.

[46]  J. Kornhauser,et al.  PhosphoSite: A bioinformatics resource dedicated to physiological protein phosphorylation , 2004, Proteomics.

[47]  Oliver Kerscher,et al.  SUMO junction—what's your function? , 2007, EMBO reports.

[48]  Liangjiang Wang,et al.  Predicting protein sumoylation sites from sequence features , 2011, Amino Acids.