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Kosinski Group

In-cell Structural Systems Biology of Infection

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 viruses and parasites using structural and systems biology approaches.

Research Projects

1) Integrative structural modeling of macromolecular complexes and AI-based structure prediction.

We develop and apply computational methods for modeling macromolecular complexes by integrating AI-based structure prediction, electron microscopy, crosslinking, and other data. We have built models of one of the largest complexes in the cell – the nuclear pore complex from humans (Nature, 2015; Science, 2016, Science, 2022) and other species (Nature Communications, 2018; Nature, 2020; Science, 2021). We also collaborate on other complexes (e.g., EMBO Reports, 2017, Science Advances, 2019, Protein Science, 2023; Nature Communications, 2023; JACS, 2023) and membrane complexes involved in malaria (Plasmofraction project). Our modeling and analysis methods are available in various software packages, including Assembline and AlphaPulldown.

2) In-cell structural biology

We develop and apply methods for structural biology in cells, primarily based on cryogenic electron tomography (cryo-ET) data. Our methods include ColabSeg software for membrane segmentation and PyTME, an ultrafast and flexible template-matching engine. We also apply in-cell cryo-ET to study influenza A virus infection and the cell biology of the Giardia lamblia parasite. Within our recent ERC Synergy Grant, we will push the development of modeling and cryo-ET analysis methods to fundamentally redefine in-cell cryo-ET data mining as an integrative structural modeling problem.

3) Integrative pathway modeling of viral infection cycles

During infection, viruses undergo complex life cycles, interact with the molecular systems of their hosts, and disturb and hijack host molecular machines for their own purposes. We aim to create comprehensive multiscale 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 proteomics, advanced fluorescence microscopy, and cryo-electron tomography. Currently, we focus on the influenza A virus in our own lab and the Lassa virus in collaboration.

Research Team

12

Group Leader

Dr. Jan Kosinski
Phone:+49 40 8998 87573

E-Mail

Postdoctoral Scientist

Dr. Lenka Cernikova
Phone:+49 40 8998 87578

E-Mail

PhD Student

Konstantin Gilep
Phone:+49 40 8998 87578

E-Mail

PhD Student

Iuliia Kotova
Phone:+49 40 8998 87578

E-Mail

PhD Student

Simon Hans Lilje
Phone:+49 40 8998 87578

E-Mail

Senior Technical Officer

Dr. Dmitry Molodenskiy
Phone:+49 40 8998 87574

E-Mail

Visiting PostDoc

Thomas Naake
Phone:+49 40 8998 87578

E-Mail

Intern

Stefanie Rössler

E-Mail

Postdoctoral Scientist

Dr. Marc Siggel
Phone:+49 40 8998 87574

E-Mail

Laboratory Officer

Dr. Ying Wang
Phone:+49 40 8998 87578

E-Mail

PhD Student

Dingquan Yu
Phone:+49 040 8998 87580

E-Mail

Postdoctoral Scientist

Dr. Daniel Ziemianowicz
Phone:+49 040 8998 87578

E-Mail

Publications

2024

Siggel M, Jensen RK, Maurer VJ, Mahamid J, Kosinski J (2024) ColabSeg: An interactive tool for editing, processing, and visualizing membrane segmentations from cryo-ET data. J Struct Biol. 108067. doi: 10.1016/j.jsb.2024.108067.

2023

Sänger L, Williams HM, Yu D, Vogel D, Kosinski J, Rosenthal M, Uetrecht C (2023) RNA to Rule Them All: Critical Steps in Lassa Virus Ribonucleoparticle Assembly and Recruitment.  J Am Chem Soc. doi: 10.1021/jacs.3c07325.

Custódio TF, Killer M, Yu D, Puente V, Teufel DP, Pautsch A, Schnapp G, Grundl M, Kosinski J, Löw C (2023) Molecular basis of TASL recruitment by the peptide/histidine transporter 1, PHT1.  Nat Commun. 14(1):5696. doi: 10.1038/s41467-023-41420-5.

Sitarska E, Almeida SD, Beckwith MS, Stopp J, Czuchnowski J, Siggel M, Roessner R, Tschanz A, Ejsing C, Schwab Y, Kosinski J, Sixt M, Kreshuk A, Erzberger A, Diz-Muñoz A (2023) Sensing their plasma membrane curvature allows migrating cells to circumvent obstacles.  Nat Commun. 14(1):5644. doi: 10.1038/s41467-023-41173-1.

Meier K, Thorkelsson SR, Durieux Trouilleton Q, Vogel D, Yu D, Kosinski J, Cusack S, Malet H, Grünewald K, Quemin ERJ, Rosenthal M (2023) Structural and functional characterization of the Sin Nombre virus L protein. PLoS Pathog. 19(8):e1011533. doi: 10.1371/journal.ppat.1011533.

Wolf K, Kosinski J, Gibson TJ, Wesch N, Dötsch V, Genuardi M, Cordisco EL, Zeuzem S, Brieger A, Plotz G (2023) A conserved motif in the disordered linker of human MLH1 is vital for DNA mismatch repair and its function is diminished by a cancer family mutation. Nucleic Acids Res. gkad418. doi: 10.1093/nar/gkad418

Jaciuk M, Scherf D, Kaszuba K, Gaik M, Rau A, Kościelniak A, Krutyhołowa R, Rawski M, Indyka P, Graziadei A, Chramiec-Głąbik A, Biela A, Dobosz D, Lin TY, Abbassi NE, Hammermeister A, Rappsilber J, Kosinski J, Schaffrath R, Glatt S (2023) Cryo-EM structure of the fully assembled Elongator complex. Nucleic Acids Res. 51(5):2011-2032. doi: 10.1093/nar/gkac1232.

Ferreira JL, Pražák V, Vasishtan D, Siggel M, Hentzschel F, Binder AM, Pietsch E, Kosinski J, Frischknecht F, Gilberger TW, Grünewald K (2023) Variable microtubule architecture in the malaria parasite. Nat Commun. 14(1):1216. doi: 10.1038/s41467-023-36627-5.

Flacht L, Lunelli M, Kaszuba K, Chen ZA, O' Reilly FJ, Rappsilber J, Kosinski J, Kolbe M (2023) Integrative structural analysis of the type III secretion system needle complex from Shigella flexneri. Protein Sci.e4595. doi: 10.1002/pro.4595

2022

Ziemianowicz DS, Kosinski J (2022) New opportunities in integrative structural modeling. Curr Opin Struct Biol. 77:102488. doi: 10.1016/j.sbi.2022.102488.

Yu D, Chojnowski G, Rosenthal M, Kosinski J (2022) AlphaPulldown – a Python package for protein-protein interaction screens using AlphaFold-Multimer (2022) Bioinformatics. btac749. doi: 10.1093/bioinformatics/btac749

Mosalaganti S, Obarska-Kosinska A, Siggel M, Taniguchi R, Turoňová B, Zimmerli CE, Buczak K, Schmidt FH, Margiotta E, Mackmull MT, Hagen WJH, Hummer G, Kosinski J, Beck M (2022) AI-based structure prediction empowers integrative structural analysis of human nuclear pores. Science. 376(6598):eabm9506. doi: 10.1126/science.abm9506.

2021

Rantos V, Karius K, Kosinski J (2021) Integrative structural modeling of macromolecular complexes using Assembline. Nat Protoc. doi: 10.1038/s41596-021-00640-z

Zimmerli CE, Allegretti M, Rantos V, Goetz SK, Obarska-Kosinska A, Zagoriy I, Halavatyi A, Hummer G, Mahamid J, Kosinski J, Beck M (2021) Nuclear pores dilate and constrict in cellulo. Science. 10.1126/science.abd9776. doi: 10.1126/science.abd9776

Masarati G, Landau M, Ben-Tal N, Lupas A, Kosloff M, Kosinski J (2021) Integrative structural biology in the era of accurate structure prediction. J Mol Biol.167127. doi: 10.1016/j.jmb.2021.167127

Beckham KSH, Ritter C, Chojnowski G, Ziemianowicz DS, Mullapudi E, Rettel M, Savitski MM, Mortensen SA, Kosinski J, Wilmanns M. (2021) Structure of the mycobacterial ESX-5 type VII secretion system pore complex. Sci Adv. 7(26):eabg9923. doi: 10.1126/sciadv.abg9923.

2020

Pazicky S, Dhamotharan K, Kaszuba K, Mertens HDT, Gilberger T, Svergun D, Kosinski J, Weininger U, Löw C (2020) Structural role of essential light chains in the apicomplexan glideosome. Commun Biol.3(1):568. doi: 10.1038/s42003-020-01283-8.

Vorländer MK, Jungblut A, Karius K, Baudin F, Grötsch H, Kosinski J, Müller CW (2020) Structure of the TFIIIC subcomplex τA provides insights into RNA polymerase III pre-initiation complex formation. Nat Commun.11(1):4905. doi: 10.1038/s41467-020-18707-y

Allegretti M, Zimmerli CE, Rantos V, Wilfling F, Ronchi P, Fung HKH, Lee CW, Hagen W, Turoňová B, Karius K, Börmel M, Zhang X, Müller CW, Schwab Y, Mahamid J, Pfander B, Kosinski J, Beck M (2020) In-cell architecture of the nuclear pore and snapshots of its turnover. Nature. doi.org/10.1038/s41586-020-2670-5

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.

Software

AlphaPulldown

A Python package that streamlines protein-protein interaction screens and high-throughput modelling of higher-order oligomers using AlphaFold-Multimer

Assembline

Pipeline for integrative structural modeling of macromolecular complexes

ColabSeg

An interactive tool for editing, processing, and visualizing membrane segmentations from cryo-ET data

PyTME

The programming library and software for template matching on electron microscopy data.

Xlink Analyzer

An interactive software for visualising cross-links on structures and analysing how the structures agree with the cross-links.

Programming libraries and other packages

Relax

Scripts to minimize macromolecular structures, for example unrelaxed AlphaFold models. Producing nice PDB files, and keeping original chain IDs. Keeping the PDB in the original reference frame. Optionally resolving side chains threading rings of aromatic side chains.

efitter

A wrapper for running UCSF Chimera Fit in Map global search from command line plus statistical analysis. This is the first step of Assembline pipeline but can be also used separately as an EM fitting program. Gives p-values for your fits!

Fitter

Code for fast EM fitting and more.

pdb_utils

Scripts for dealing with PDB files – renumber residues, rename chains, cut and merge PDB files and many others without modifying parts that do not need to be modified.

pyxlinks

A Python package for dealing with cross-linking/MS data. Used by Xlink Analyzer but can be used standalone too.

modeling_utils

modeling_utils provide a modeling script that give a sequence alignment automates the most common tasks in homology modeling and provides utilities to prepare the input.

It is quite a ground-braking script because it features:

  • oligomeric/multi-chain modeling and multiple templates
  • optional removal of tails and inserts
  • and keeping the correct residue numbering with the above
  • setting unique chain ids to the output chains
  • provides command line options for controlling optimization levels and number of output models

A useful programming library is also included.

alphafold_howto

Collection of SLURM script examples for running AlphaFold and RoseTTAFold. Adjusted to EMBL compute cluster but could work for you too with some adjustments.