Skip to main content
SpringerLink
Log in

Binding properties of SUMO-interacting motifs (SIMs) in yeast

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

Abstract

Small ubiquitin-like modifier (SUMO) conjugation and interaction play an essential role in many cellular processes. A large number of yeast proteins is known to interact non-covalently with SUMO via short SUMO-interacting motifs (SIMs), but the structural details of this interaction are yet poorly characterized. In the present work, sequence analysis of a large dataset of 148 yeast SIMs revealed the existence of a hydrophobic core binding motif and a preference for acidic residues either within or adjacent to the core motif. Thus the sequence properties of yeast SIMs are highly similar to those described for human. Molecular dynamics simulations were performed to investigate the binding preferences for four representative SIM peptides differing in the number and distribution of acidic residues. Furthermore, the relative stability of two previously observed alternative binding orientations (parallel, antiparallel) was assessed. For all SIMs investigated, the antiparallel binding mode remained stable in the simulations and the SIMs were tightly bound via their hydrophobic core residues supplemented by polar interactions of the acidic residues. In contrary, the stability of the parallel binding mode is more dependent on the sequence features of the SIM motif like the number and position of acidic residues or the presence of additional adjacent interaction motifs. This information should be helpful to enhance the prediction of SIMs and their binding properties in different organisms to facilitate the reconstruction of the SUMO interactome.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Jones S, Thornton JM (1995) Protein-protein interactions: a review of protein dimer structures. Prog Biophys Mol Biol 63:31–65

    Article  CAS  Google Scholar 

  2. Lo Conte L, Chothia C, Janin J (1999) The atomic structure of protein-protein recognition sites. J Mol Biol 285:2177–2198

    Article  CAS  Google Scholar 

  3. Jones S, Thornton JM (1996) Principles of protein-protein interactions. Proc Natl Acad Sci U S A 93:13–20

    Article  CAS  Google Scholar 

  4. Nooren IM, Thornton JM (2003) Diversity of protein-protein interactions. EMBO J 22:3486–3492

    Article  CAS  Google Scholar 

  5. Pawson T, Nash P (2003) Assembly of cell regulatory systems through protein interaction domains. Science 300:445–452

    Article  CAS  Google Scholar 

  6. Aloy P, Russell RB (2004) Ten thousand interactions for the molecular biologist. Nat Biotechnol 22:1317–1321

    Article  CAS  Google Scholar 

  7. Gietz RD, Triggs-Raine B, Robbins A, Graham KC, Woods RA (1997) Identification of proteins that interact with a protein of interest: applications of the yeast two-hybrid system. Mol Cell Biochem 172:67–79

    Article  CAS  Google Scholar 

  8. Young KH (1998) Yeast two-hybrid: so many interactions, (in) so little time. Biol Reprod 58:302–311

    Article  CAS  Google Scholar 

  9. Aebersold R, Mann M (2003) Mass spectrometry-based proteomics. Nature 422:198–207

    Article  CAS  Google Scholar 

  10. Gavin AC, Superti-Furga G (2003) Protein complexes and proteome organization from yeast to man. Curr Opin Chem Biol 7:21–27

    Article  CAS  Google Scholar 

  11. Yu H, Braun P, Yildirim MA, Lemmens I, Venkatesan K, Sahalie J, Hirozane-Kishikawa T, Gebreab F, Li N, Simonis N, Hao T, Rual JF, Dricot A, Vazquez A, Murray RR, Simon C, Tardivo L, Tam S, Svrzikapa N, Fan C, de Smet AS, Motyl A, Hudson ME, Park J, Xin X, Cusick ME, Moore T, Boone C, Snyder M, Roth FP, Barabasi AL, Tavernier J, Hill DE, Vidal M (2008) High-quality binary protein interaction map of the yeast interactome network. Science 322:104–110

    Article  CAS  Google Scholar 

  12. Gareau JR, Lima CD (2010) The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition. Nat Rev Mol Cell Biol 11:861–871

    Article  CAS  Google Scholar 

  13. Wimmer P, Schreiner S, Dobner T (2012) Human pathogens and the host cell SUMOylation system. J Virol 86:642–654

    Article  CAS  Google Scholar 

  14. Cuchet D, Sykes A, Nicolas A, Orr A, Murray J, Sirma H, Heeren J, Bartelt A, Everett RD (2010) PML isoforms I and II participate in PML-dependent restriction of HSV-1 replication. J Cell Sci 124:280–291

    Article  Google Scholar 

  15. Hay RT (2001) Protein modification by SUMO. Trends Biochem Sci 26:332–333

    Article  CAS  Google Scholar 

  16. Müller S, Hoege C, Pyrowolakis G, Jentsch S (2001) SUMO, ubiquitin’s mysterious cousin. Nat Rev Mol Cell Biol 2:202–210

    Article  Google Scholar 

  17. Namanja AT, Li YJ, Su Y, Wong S, Lu J, Colson LT, Wu C, Li SS, Chen Y (2012) Insights into high affinity small ubiquitin-like modifier (SUMO) recognition by SUMO-interacting motifs (SIMs) revealed by a combination of NMR and peptide array analysis. J Biol Chem 287:3231–3240

    Article  CAS  Google Scholar 

  18. Reverter D, Lima CD (2005) Insights into E3 ligase activity revealed by a SUMO-RanGAP1-Ubc9-Nup358 complex. Nature 435:687–692

    Article  CAS  Google Scholar 

  19. Song J, Zhang Z, Hu W, Chen Y (2005) Small ubiquitin-like modifier (SUMO) recognition of a SUMO binding motif: a reversal of the bound orientation. J Biol Chem 280:40122–40129

    Article  CAS  Google Scholar 

  20. Sekiyama N, Ikegami T, Yamane T, Ikeguchi M, Uchimura Y, Baba D, Ariyoshi M, Tochio H, Saitoh H, Shirakawa M (2008) Structure of the small ubiquitin-like modifier (SUMO)-interacting motif of MBD1-containing chromatin-associated factor 1 bound to SUMO-3. J Biol Chem 283:35966–35975

    Article  CAS  Google Scholar 

  21. Chang CC, Naik MT, Huang YS, Jeng JC, Liao PH, Kuo HY, Ho CC, Hsieh YL, Lin CH, Huang NJ, Naik NM, Kung CC, Lin SY, Chen RH, Chang KS, Huang TH, Shih HM (2011) Structural and functional roles of Daxx SIM phosphorylation in SUMO paralog-selective binding and apoptosis modulation. Mol Cell 42:62–74

    Article  CAS  Google Scholar 

  22. Xu Y, Plechanovova A, Simpson P, Marchant J, Leidecker O, Kraatz S, Hay RT, Matthews SJ (2014) Structural insight into SUMO chain recognition and manipulation by the ubiquitin ligase RNF4. Nat Commun 5:4217

    CAS  Google Scholar 

  23. Hecker CM, Rabiller M, Haglund K, Bayer P, Dikic I (2006) Specification of SUMO1- and SUMO2-interacting motifs. J Biol Chem 281:16117–16127

    Article  CAS  Google Scholar 

  24. Kerscher O (2007) SUMO junction-what’s your function? New insights through SUMO-interacting motifs. EMBO Rep 8:550–555

    Article  CAS  Google Scholar 

  25. Lin DY, Huang YS, Jeng JC, Kuo HY, Chang CC, Chao TT, Ho CC, Chen YC, Lin TP, Fang HI, Hung CC, Suen CS, Hwang MJ, Chang KS, Maul GG, Shih HM (2006) Role of SUMO-interacting motif in Daxx SUMO modification, subnuclear localization, and repression of sumoylated transcription factors. Mol Cell 24:341–354

    Article  CAS  Google Scholar 

  26. Stehmeier P, Muller S (2009) Phospho-regulated SUMO interaction modules connect the SUMO system to CK2 signaling. Mol Cell 33:400–409

    Article  CAS  Google Scholar 

  27. Chang PC, Izumiya Y, Wu CY, Fitzgerald LD, Campbell M, Ellison TJ, Lam KS, Luciw PA, Kung HJ (2010) Kaposi’s sarcoma-associated herpesvirus (KSHV) encodes a SUMO E3 ligase that is SIM-dependent and SUMO-2/3-specific. J Biol Chem 285:5266–5273

    Article  CAS  Google Scholar 

  28. Meulmeester E, Kunze M, Hsiao HH, Urlaub H, Melchior F (2008) Mechanism and consequences for paralog-specific sumoylation of ubiquitin-specific protease 25. Mol Cell 30:610–619

    Article  CAS  Google Scholar 

  29. Cai Q, Cai S, Zhu, C, Verma, SC, Choi JY, Robertson ES (2013) A Unique SUMO-2-Interacting Motif within LANA Is Essential for KSHV Latency. PLoS Pathog 9:e1003750

  30. Makhnevych T, Sydorskyy Y, Xin X, Srikumar T, Vizeacoumar FJ, Jeram SM, Li Z, Bahr S, Andrews BJ, Boone C, Raught B (2009) Global map of SUMO function revealed by protein-protein interaction and genetic networks. Mol Cell 33:124–135

    Article  CAS  Google Scholar 

  31. Sung MK, Lim G, Yi DG, Chang YJ, Yang EB, Lee K, Huh WK (2013) Genome-wide bimolecular fluorescence complementation analysis of SUMO interactome in yeast. Genome Res 23:736–746

    Article  CAS  Google Scholar 

  32. Srikumar T, Lewicki MC, Raught B (2013) A global S. cerevisiae small ubiquitin-related modifier (SUMO) system interactome. Mol Syst Biol 9:668

    Article  CAS  Google Scholar 

  33. Hannich JT, Lewis A, Kroetz MB, Li SJ, Heide H, Emili A, Hochstrasser M (2005) Defining the SUMO-modified proteome by multiple approaches in Saccharomyces cerevisiae. J Biol Chem 280:4102–4110

    Article  CAS  Google Scholar 

  34. Armstrong AA, Mohideen F, Lima CD (2012) Recognition of SUMO-modified PCNA requires tandem receptor motifs in Srs2. Nature 483:59–63

    Article  CAS  Google Scholar 

  35. Kolesar P, Sarangi P, Altmannova V, Zhao X, Krejci L (2012) Dual roles of the SUMO-interacting motif in the regulation of Srs2 sumoylation. Nucleic Acids Res 40:7831–7843

    Article  CAS  Google Scholar 

  36. Gilbreth RN, Truong K, Madu I, Koide A, Wojcik JB, Li NS, Piccirilli JA, Chen Y, Koide S (2011) Isoform-specific monobody inhibitors of small ubiquitin-related modifiers engineered using structure-guided library design. Proc Natl Acad Sci U S A 108:7751–7756

    Article  CAS  Google Scholar 

  37. Crooks GE, Hon G, Chandonia JM, Brenner SE (2004) WebLogo: a sequence logo generator. Genome Res 14:1188–1190

    Article  CAS  Google Scholar 

  38. Guex N, Peitsch MC (1997) SWISS-MODEL and the Swiss-Pdb Viewer: an environment for comparative protein modeling. Electrophoresis 18:2714–2723

    Article  CAS  Google Scholar 

  39. Mossessova E, Lima CD (2000) Ulp1-SUMO crystal structure and genetic analysis reveal conserved interactions and a regulatory element essential for cell growth in yeast. Mol Cell 5:865–876

    Article  CAS  Google Scholar 

  40. Case DA, Darden TA, Cheatham TEI, Simmerling CL, Wang J, Duke RE, Luo R, Walker RC, Zhang W, Merz KM, Roberts B, Hayik S, Roitberg A, Seabra G, Swails J, Goetz AW, Kolossváry I, Wong KF, Paesani F, Vanicek J, Wolf RM, Liu J, Wu X, Brozell SR, Steinbrecher T, Gohlke H, Cai Q, Ye X, Wang J, Hsieh M-J, Cui G, Roe DR, Mathews DH, Seetin MG, Salomon-Ferrer R, Sagui C, Babin V, Luchko T, Gusarov S, Kovalenko A, Kollman PA (2012) AMBER 12. University of California, San Francisco

    Google Scholar 

  41. Hornak V, Abel R, Okur A, Strockbine B, Roitberg A, Simmerling CL (2006) Comparison of multiple Amber force fields and development of improved protein backbone parameters. Proteins 65:712–725

    Article  CAS  Google Scholar 

  42. Jardin C, Horn AHC, Schürer G, Sticht H (2008) Insight into the phosphoryl transfer of the Escherichia coli glucose phosphotransferase system from QM/MM simulations. J Phys Chem B 112:13391–13400

    Article  CAS  Google Scholar 

  43. Mazumder ED, Jardin C, Vogel B, Heck E, Scholz B, Lengenfelder D, Sticht H, Ensser A (2012) A molecular model for the differential activation of STAT3 and STAT6 by the herpesviral oncoprotein tip. PLoS One 7:e34306

    Article  CAS  Google Scholar 

  44. Jardin C, Sticht H (2012) Identification of the structural features that mediate binding specificity in the recognition of STAT proteins by dual-specificity phosphatases. J Biomol Struct Dyn 29:777–792

    Article  CAS  Google Scholar 

  45. Ryckaert JP, Ciccotti G, Berendsen HJC (1977) Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Physiol 23:327–341

    Article  CAS  Google Scholar 

  46. Humphrey W, Dalke A, Schulten K (1996) VMD: Visual molecular dynamics. J Mol Graph 14:33–38

    Article  CAS  Google Scholar 

  47. Accelrys Software Inc (2004) Discovery Studio Modeling Environment, Release 2.1. Accelrys Inc, San Diego

    Google Scholar 

  48. Dinkel H, Van Roey K, Michael S, Davey NE, Weatheritt RJ, Born D, Speck T, Kruger D, Grebnev G, Kuban M, Strumillo M, Uyar B, Budd A, Altenberg B, Seiler M, Chemes LB, Glavina J, Sanchez IE, Diella F, Gibson TJ (2014) The eukaryotic linear motif resource ELM: 10 years and counting. Nucleic Acids Res 42:D259–266

    Article  CAS  Google Scholar 

  49. Escobar-Cabrera E, Okon M, Lau DK, Dart CF, Bonvin AM, McIntosh LP (2011) Characterizing the N- and C-terminal small ubiquitin-like modifier (SUMO)-interacting motifs of the scaffold protein DAXX. J Biol Chem 286:19816–19829

    Article  CAS  Google Scholar 

  50. Selzer T, Albeck S, Schreiber G (2000) Rational design of faster associating and tighter binding protein complexes. Nat Struct Biol 7:537–541

    Article  CAS  Google Scholar 

  51. Kiel C, Selzer T, Shaul Y, Schreiber G, Herrmann C (2004) Electrostatically optimized Ras-binding Ral guanine dissociation stimulator mutants increase the rate of association by stabilizing the encounter complex. Proc Natl Acad Sci U S A 101:9223–9228

    Article  CAS  Google Scholar 

Download references

Acknowledgments

The project was funded by the Deutsche Forschungsgemeinschaft (SFB796, project A2) to HS. The authors thank Melanie Schneider and Jakob Bader for fruitful discussions, as well as Thomas Zeiser from the High Performance Computing group of the Regionales Rechenzentrum Erlangen (RRZE) for providing optimized AMBER executables.

Author information

Authors and Affiliations

  1. Bioinformatik, Institut für Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstr. 17, 91054, Erlangen, Germany

    Christophe Jardin, Anselm H. C. Horn & Heinrich Sticht

Authors
  1. Christophe Jardin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anselm H. C. Horn
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heinrich Sticht
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Heinrich Sticht.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Figs. S1–S4

Showing details of the control simulations, which used the alternative ySUMO template, are available as supplementary material. (DOCX 3022 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jardin, C., Horn, A.H.C. & Sticht, H. Binding properties of SUMO-interacting motifs (SIMs) in yeast. J Mol Model 21, 50 (2015). https://doi.org/10.1007/s00894-015-2597-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00894-015-2597-1

Keywords

Search

Navigation