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Kosinski Group

Integrative Modeling of Infection Cycles

Dr. Jan Kosinski

Group Leader

+49 40 8998 87573
jan.kosinski@cssb-hamburg.de

Home Institute

European Molecular Biology Laboratory
www.embl.de/

We investigate the structure of macromolecular complexes using integrative structural modeling based on data from techniques such as electron microscopy and crosslinking. We also study viral infection cycles to identify new infection pathways and virus-host interactions by pathway modeling and wet-lab experiments.

Research Projects

Integrative structural modeling

Integrative structural modeling allows determining the structure of large macromolecular complexes by combining experimental data from electron microscopy, crosslinking, SAXS, and other techniques. It involves representing the data as restraints, generating structural conformations that satisfy these restraints using optimization procedures, and analysing the resulting ensembles of models. We develop methods for all these stages as well as work on automated modeling pipelines (Kosinski, 2016) and graphical interfaces such as XlinkAnalyzer software. We then apply our methods to collaborative projects.

Integrative pathway modeling of viral infection cycles

During infection, pathogens undergo complex life cycles, interact with molecular systems of their hosts, and disturb and hijack host molecular machines for their own purposes. We aim at creating comprehensive multi-scale models of entire infection cycles to discover host-pathogen interactions and identify which of them are the most crucial for infection. To this end, we integrate systems biology data with structural information using novel pathway modeling methods. We then characterize the most promising interactions using bioinformatics and wet-lab experiments.

We currently focus on the infection cycle of the influenza virus. In addition to computational pathway modeling of the influenza infection cycle, we study this virus both experimentally in our own lab (Biosafety Level 2) to collect additional data and validate our computational hypotheses.

Nuclear pore complex

The nuclear pore complex (NPC) is responsible for the transport between the cytoplasm and the nucleus. It is one of the largest complexes in the cell. Recently, together with Martin Beck’s group at EMBL Heidelberg, we applied our integrative methods to build a near-atomic model of the human NPC, based on data from cryo-electron tomography and crosslinking mass spectrometry (von Appen, 2015; Kosinski, 2016). In collaboration with the Beck group, we continue working on the NPC to extend the model, understand its structure in more detail, and characterize its evolution.

Bacterial secretion systems

Many bacterial pathogens use multi-subunit secretion systems to translocate effector proteins across the cell wall into the host cell. Understanding their structure could reveal how these molecular machines work and help in development of antimicrobial therapeutics. We collaborate on two types of these systems, Type VII of Mycobacteria (T7SS, collaboration with Matthias Wilmanns) and Type III of Shigella flexner (T3SS, CSSB Seed Project with Michael Kolbe from CSSB), contributing our integrative modeling expertise.

 

FUTURE PROJECTS AND GOALS

  • Integrative structural modeling of macromolecular complexes and cellular landscapes
  • Development and application of methods for integrative modeling of infection cycles
  • Accelerating discovery of host-pathogen interactions most promising for therapeutic intervention through pathway modeling
  • Mechanisms of subversion of the nuclear pore complex by pathogens

Research Team

7

Group Leader

Dr. Jan Kosinski
Phone:+49 40 8998 87573

E-Mail

Dr. Biruhalem Taye Beyene
Phone:+49 40 8998 87578

E-Mail

Dr. Karolina Drazkowska
Phone:+49 40 8998 87578

E-Mail

Kai Karius
Phone:+49 40 8998 87574

E-Mail

Dr. Karol Kaszuba
Phone:+49 40 8998 87578

E-Mail

Vasileios Rantos
Phone:+49 40 8998 87574

E-Mail

Dr. Nikenza Viceconte
Phone:+49 40 8998 87578

E-Mail

Publications

2019

Dauden MI, Jaciuk M, Weis F, Lin TY, Kleindienst C, Abbassi NEH, Khatter H, Krutyhołowa R, Breunig KD, Kosinski J, Müller CW, Glatt S (2019) Molecular basis of tRNA recognition by the Elongator complex. Sci Adv 5: eaaw2326 doi: 10.1126/sciadv.aaw2326

Ural-Blimke Y, Flayhan A, Strauss J, Rantos V, Bartels K, Nielsen R, Pardon E, Steyaert J, Kosinski J, Quistgaard EM, Löw C (2019) Structure of Prototypic Peptide Transporter DtpA from E. coli in Complex with Valganciclovir Provides Insights into Drug Binding of Human PepT1. J Am Chem Soc 141: 2404-2412 doi: 10.1021/jacs.8b11343

2018

Mosalaganti S, Kosinski J, Albert S, Schaffer M, Strenkert D, Salomé PA, Merchant SS, Plitzko JM, Baumeister W, Engel BD, Beck M (2018) In situ architecture of the algal nuclear pore complex. Nat Commun 9: 2361 doi: 10.1038/s41467-018-04739-y

Mathieson T, Franken H, Kosinski J, Kurzawa N, Zinn N, Sweetman G, Poeckel D, Ratnu VS, Schramm M, Becher I, Steidel M, Noh KM, Bergamini G, Beck M, Bantscheff M, Savitski MM (2018) Systematic analysis of protein turnover in primary cells. Nat Commun 9: 689 doi: 10.1038/s41467-018-03106-1

Beck M, Mosalaganti S, Kosinski J (2018) From the resolution revolution to evolution: structural insights into the evolutionary relationships between vesicle coats and the nuclear pore. Curr Opin Struct Biol 52: 32-40 doi: 10.1016/j.sbi.2018.07.012

2017

Teimer R, Kosinski J, von Appen A, Beck M, Hurt E (2017) A short linear motif in scaffold Nup145C connects Y-complex with pre-assembled outer ring Nup82 complex. Nat Commun 8: 1107 doi: 10.1038/s41467-017-01160-9

Sadian Y, Tafur L, Kosinski J, Jakobi AJ, Wetzel R, Buczak K, Hagen WJ, Beck M, Sachse C, Müller CW (2017) Structural insights into transcription initiation by yeast RNA polymerase I. EMBO J 36: 2698-2709 doi: 10.15252/embj.201796958

Dauden MI, Kosinski J, Kolaj-Robin O, Desfosses A, Ori A, Faux C, Hoffmann NA, Onuma OF, Breunig KD, Beck M, Sachse C, Séraphin B, Glatt S, Müller CW (2017) Architecture of the yeast Elongator complex. EMBO Rep 18: 264-279 doi: 10.15252/embr.201643353

2016

Thierry E, Guilligay D, Kosinski J, Bock T, Gaudon S, Round A, Pflug A, Hengrung N, El Omari K, Baudin F, Hart DJ, Beck M, Cusack S (2016) Influenza Polymerase Can Adopt an Alternative Configuration Involving a Radical Repacking of PB2 Domains. Mol Cell 61: 125-137 doi: 10.1016/j.molcel.2015.11.016

Kosinski J, Mosalaganti S, von Appen A, Teimer R, DiGuilio AL, Wan W, Bui KH, Hagen WJ, Briggs JA, Glavy JS, Hurt E, Beck M (2016) Molecular architecture of the inner ring scaffold of the human nuclear pore complex. Science 352: 363-365 doi: 10.1126/science.aaf0643

Hoffmann NA, Sadian Y, Tafur L, Kosinski J, Müller CW (2016) Specialization versus conservation: How Pol I and Pol III use the conserved architecture of the pre-initiation complex for specialized transcription. Transcription 7: 127-132 doi: 10.1080/21541264.2016.1203628

Ferber M, Kosinski J, Ori A, Rashid UJ, Moreno-Morcillo M, Simon B, Bouvier G, Batista PR, Müller CW, Beck M, Nilges M (2016) Automated structure modeling of large protein assemblies using crosslinks as distance restraints. Nat Methods 13: 515-520 doi: 10.1038/nmeth.3838

Bertipaglia C, Schneider S, Jakobi AJ, Tarafder AK, Bykov YS, Picco A, Kukulski W, Kosinski J, Hagen WJ, Ravichandran AC, Wilmanns M, Kaksonen M, Briggs JA, Sachse C (2016) Higher-order assemblies of oligomeric cargo receptor complexes form the membrane scaffold of the Cvt vesicle. EMBO Rep 17: 1044-1060 doi: 10.15252/embr.201541960

2015

von Appen A, Kosinski J, Sparks L, Ori A, DiGuilio AL, Vollmer B, Mackmull MT, Banterle N, Parca L, Kastritis P, Buczak K, Mosalaganti S, Hagen W, Andres-Pons A, Lemke EA, Bork P, Antonin W, Glavy JS, Bui KH, Beck M (2015) In situ structural analysis of the human nuclear pore complex. Nature 526: 140-143 doi: 10.1038/nature15381

Kosinski J, von Appen A, Ori A, Karius K, Müller CW, Beck M (2015) Xlink Analyzer: software for analysis and visualization of cross-linking data in the context of three-dimensional structures. J Struct Biol 189: 177-183 doi: 10.1016/j.jsb.2015.01.014

Hoffmann NA, Jakobi AJ, Moreno-Morcillo M, Glatt S, Kosinski J, Hagen WJ, Sachse C, Müller CW (2015) Molecular structures of unbound and transcribing RNA polymerase III. Nature 528: 231-236 doi: 10.1038/nature16143

2013

Kosinski J*, Barbato A*, Tramontano A (2013) MODexplorer: an integrated tool for exploring protein sequence, structure and function relationships. Bioinformatics 29: 953–4.

2012

Barbato A, Benkert P, Schwede T, Tramontano A, Kosinski J, (2012) Improving your target-template alignment with MODalign. Bioinformatics 28: 1038–9.

2011

Milanowska K, Krwawicz J, Papaj G, Kosinski J, Poleszak K, Lesiak J, Osinska E, Rother K, Bujnicki JM (2011) REPAIRtoire--a database of DNA repair pathways. Nucleic Acids Res. 39: D788–92.

2010

Kosinski J, Hinrichsen I, Bujnicki JM, Friedhoff P, Plotz G (2010) Identification of Lynch syndrome mutations in the MLH1-PMS2 interface that disturb dimerization and mismatch repair. Hum. Mutat. 31: 975–82.

Pukáncsik M, Békési A, Klement E, Hunyadi-Gulyás E, Medzihradszky KF, Kosinski J, Bujnicki JM, Alfonso C, Rivas G, Vértessy BG (2010) Physiological truncation and domain organization of a novel uracil-DNA-degrading factor. FEBS J. 277: 1245–59.

2008

Kosinski J*, Plotz G*, Guarné A, Bujnicki JM, Friedhoff P (2008) The PMS2 subunit of human MutLalpha contains a metal ion binding domain of the iron-dependent repressor protein family. J. Mol. Biol. 382: 610–27.

2007

Chovancová E, Kosinski J, Bujnicki JM, Damborský J (2007) Phylogenetic analysis of haloalkane dehalogenases. Proteins 67: 305–16.

Kosinski J, Kubareva E, Bujnicki JM (2007) A model of restriction endonuclease MvaI in complex with DNA: a template for interpretation of experimental data and a guide for specificity engineering. Proteins 68: 324–36.

Liu Y, Li Z, Lin Q, Kosinski J, Seetharaman J, Bujnicki JM, Sivaraman J, Hew C-L (2007) Structure and evolutionary origin of Ca(2+)-dependent herring type II antifreeze protein. PLoS One 2: e548.

Miyazono K, Watanabe M, Kosinski J, Ishikawa K, Kamo M, Sawasaki T, Nagata K, Bujnicki JM, Endo Y, Tanokura M, Kobayashi I (2007) Novel protein fold discovered in the PabI family of restriction enzymes. Nucleic Acids Res. 35: 1908–18.

2006

Ahrends R, Kosinski J, Kirsch D, Manelyte L, Giron-Monzon L, Hummerich L, Schulz O, Spengler B, Friedhoff P (2006) Identifying an interaction site between MutH and the C-terminal domain of MutL by crosslinking, affinity purification, chemical coding and mass spectrometry. Nucleic Acids Res. 34: 3169–80.

Skowronek KJ, Kosinski J, Bujnicki JM (2006) Theoretical model of restriction endonuclease HpaI in complex with DNA, predicted by fold recognition and validated by site-directed mutagenesis. Proteins 63: 1059–68.

Zegers I, Gigot D, van Vliet F, Tricot C, Aymerich S, Bujnicki JM, Kosinski J, Droogmans L (2006) Crystal structure of Bacillus subtilis TrmB, the tRNA (m7G46) methyltransferase. Nucleic Acids Res. 34: 1925–34.

2005

Armalyte E, Bujnicki JM, Giedriene J, Gasiunas G, Kosiński J, Lubys A (2005) Mva1269I: a monomeric type IIS restriction endonuclease from Micrococcus varians with two EcoRI- and FokI-like catalytic domains. J. Biol. Chem. 280: 41584–94.

Kosinski J, Feder M, Bujnicki JM (2005) The PD-(D/E)XK superfamily revisited: identification of new members among proteins involved in DNA metabolism and functional predictions for domains of (hitherto) unknown function. BMC Bioinformatics 6: 172.

Kosinski J, Gajda MJ, Cymerman IA, Kurowski MA, Pawlowski M, Boniecki M, Obarska A, Papaj G, Sroczynska-Obuchowicz P, Tkaczuk KL, Sniezynska P, Sasin JM, Augustyn A, Bujnicki JM, Feder M (2005) Frankenstein becomes a cyborg: the automatic recombination and realignment of fold recognition models in CASP6. Proteins 61 Suppl 7: 106–13.

Kosinski J, Steindorf I, Bujnicki JM, Giron-Monzon L, Friedhoff P (2005) Analysis of the quaternary structure of the MutL C-terminal domain. J. Mol. Biol. 351: 895–909.

2004

Ye X, O’Neil PK, Foster AN, Gajda MJ, Kosinski J, Kurowski MA, Bujnicki JM, Friedman AM, Bailey-Kellogg C (2004) Probabilistic cross-link analysis and experiment planning for high-throughput elucidation of protein structure. Protein Sci. 13: 3298–313.

2003

Kosinski J, Cymerman IA, Feder M, Kurowski MA, Sasin JM, Bujnicki JM (2003) A “Frankenstein’s monster” approach to comparative modeling: merging the finest fragments of Fold-Recognition models and iterative model refinement aided by 3D structure evaluation. Proteins 53 Suppl 6: 369–79.