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Sondermann Group

Molecular and Structural Microbiology

Prof. Dr. Holger Sondermann

Group Leader

+49 040 8998 87680

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Deutsches Elektronen-Synchrotron

Bacteria are constantly challenged with and react to changing environments. The adaptation to their complex surrounding increases survival to hostile situations such as nutrient limitation or exposure to antibiotics. We study the molecular mechanisms and signaling, from environmental input to physiological output, that control bacterial lifestyle changes often linked to host-microbe interactions and infectious disease.

Research Projects


Opportunistic bacterial pathogens cause a variety of infectious diseases. Their capability for sensing and responding to various microenvironments, particularly during the transition from a free-swimming to a sessile lifestyle (Figure 1), contributes to the establishment of chronic infections and depends on a variety of adaptational strategies. Examples include morphological variation, biofilm formation, antibiotic resistance development, and virulence gene expression, suggested to be interlinked phenotypes relying primarily on bacterial signaling. These mechanisms increase tolerance to external stresses and survival in niche environments, forming a tremendous obstacle for the efficient treatment of infections. They are equally important mechanisms for non-pathogenic bacteria that can live in commensal relationship with their environment. Understanding the architecture and regulation of signaling systems that control bacterial cell adhesion and biofilm formation is critical in the development of novel therapies and preventative interventions, while providing fundamental insight into bacterial physiology.

Central to the adaptation mechanism and the focus of our research is a bacterial second messenger, c-di-GMP, and the proteins responsible for its biosynthesis, degradation, and signal transmission (Figure 2). Bacterial genomes often encode a large number of enzymes that control cellular c-di-GMP levels and this complexity of c-di-GMP signaling networks usually scales with the capacity of a microbe to react to and colonize diverse environmental niches. While it is accepted that the multiplication of c-di-GMP-metabolizing enzymes endows the microbe with increased responsive potential to external stimuli by equipping the signaling units with diverse sensing domains, the actual ligands that modulate enzymatic activity are often unknown. Also, despite overlapping enzymatic functions within the c-di-GMP-signaling proteins, the physiological outcome associated with individual enzymes can be often unique – a poorly understood phenomenon on the molecular level. Finally, a link has been established recently between c-di-GMP signaling and a housekeeping RNase that completes the degradation of the second messenger, however the significance of connecting signaling and general RNA metabolism is an emerging field.

In our work, we integrate structural biology, biophysical and biochemical approaches, together with cell biology to elucidate fundamental molecular mechanisms that control bacterial physiology and life-style changes. While basic in nature, these studies have ultimately the potential to reveal novel Achille’s heels in pathogens associated with recalcitrant infections and, by extension, avenues for innovative therapies.

Research Team


Group Leader

Holger Sondermann
Phone:+49 040 8998 87680


Maria Garcia Garcia
Phone:+49 40 8998 87681




O'Donnell JP, Kelly CM, Sondermann H (2020) Nucleotide-Dependent Dimerization and Conformational Switching of Atlastin. Methods Mol Biol 2159: 93-113 doi: 10.1007/978-1-0716-0676-6_8

Collins AJ, Smith TJ, Sondermann H, O'Toole GA (2020) From Input to Output: The Lap/c-di-GMP Biofilm Regulatory Circuit. Annu Rev Microbiol 10.1146/annurev-micro-011520-094214


Kitts G, Giglio KM, Zamorano-Sanchez D, Park JH, Townsley L, Cooley RB, Wucher BR, Klose KE, Nadell CD, Yildiz FH, Sondermann H (2019) A Conserved Regulatory Circuit Controls Large Adhesins in Vibrio cholerae. mBio 1010.1128/mBio.02822-19

Kim SK, Lormand JD, Weiss CA, Eger KA, Turdiev H, Turdiev A, Winkler WC, Sondermann H, Lee VT (2019) A dedicated diribonucleotidase resolves a key bottleneck for the terminal step of RNA degradation. Elife 810.7554/eLife.46313

Dingemans J, Al-Feghali RE, Sondermann H, Sauer K (2019) Signal Sensing and Transduction Are Conserved between the Periplasmic Sensory Domains of BifA and SagS. mSphere 410.1128/mSphere.00442-19


Smith TJ, Sondermann H, O'Toole GA (2018) Type 1 Does the Two-Step: Type 1 Secretion Substrates with a Functional Periplasmic Intermediate. J Bacteriol 20010.1128/JB.00168-18

Smith TJ, Sondermann H, O'Toole GA (2018) Co-opting the Lap System of Pseudomonas fluorescens To Reversibly Customize Bacterial Cell Surfaces. ACS Synth Biol 7: 2612-2617 doi: 10.1021/acssynbio.8b00278

Smith TJ, Font ME, Kelly CM, Sondermann H, O'Toole GA (2018) An N-Terminal Retention Module Anchors the Giant Adhesin LapA of Pseudomonas fluorescens at the Cell Surface: a Novel Subfamily of Type I Secretion Systems. J Bacteriol 20010.1128/JB.00734-17

O'Donnell JP, Marsh HM, Sondermann H, Sevier CS (2018) Disrupted Hydrogen-Bond Network and Impaired ATPase Activity in an Hsc70 Cysteine Mutant. Biochemistry 57: 1073-1086 doi: 10.1021/acs.biochem.7b01005

O'Donnell JP, Byrnes LJ, Cooley RB, Sondermann H (2018) A hereditary spastic paraplegia-associated atlastin variant exhibits defective allosteric coupling in the catalytic core. J Biol Chem 293: 687-700 doi: 10.1074/jbc.RA117.000380

Giacalone D, Smith TJ, Collins AJ, Sondermann H, Koziol LJ, O'Toole GA (2018) Ligand-Mediated Biofilm Formation via Enhanced Physical Interaction between a Diguanylate Cyclase and Its Receptor. mBio 910.1128/mBio.01254-18

Dingemans J, Poudyal B, Sondermann H, Sauer K (2018) The Yin and Yang of SagS: Distinct Residues in the HmsP Domain of SagS Independently Regulate Biofilm Formation and Biofilm Drug Tolerance. mSphere 310.1128/mSphere.00192-18


O'Donnell JP, Cooley RB, Kelly CM, Miller K, Andersen OS, Rusinova R, Sondermann H (2017) Timing and Reset Mechanism of GTP Hydrolysis-Driven Conformational Changes of Atlastin. Structure 25: 997-1010 e1014 doi: 10.1016/j.str.2017.05.007

Krasteva PV, Sondermann H (2017) Versatile modes of cellular regulation via cyclic dinucleotides. Nat Chem Biol 13: 350-359 doi: 10.1038/nchembio.2337

Cooley RB, Sondermann H (2017) Probing Protein-Protein Interactions with Genetically Encoded Photoactivatable Cross-Linkers. Methods Mol Biol 1657: 331-345 doi: 10.1007/978-1-4939-7240-1_26

Conner JG, Zamorano-Sanchez D, Park JH, Sondermann H, Yildiz FH (2017) The ins and outs of cyclic di-GMP signaling in Vibrio cholerae. Curr Opin Microbiol 36: 20-29 doi: 10.1016/j.mib.2017.01.002


Meyer PA, Socias S, Key J, Ransey E, Tjon EC, Buschiazzo A, Lei M, Botka C, Withrow J, Neau D, Rajashankar K, Anderson KS, Baxter RH, Blacklow SC, Boggon TJ, Bonvin AM, Borek D, Brett TJ, Caflisch A, Chang CI, Chazin WJ, Corbett KD, Cosgrove MS, Crosson S, Dhe-Paganon S, Di Cera E, Drennan CL, Eck MJ, Eichman BF, Fan QR, Ferre-D'Amare AR, Fromme JC, Garcia KC, Gaudet R, Gong P, Harrison SC, Heldwein EE, Jia Z, Keenan RJ, Kruse AC, Kvansakul M, McLellan JS, Modis Y, Nam Y, Otwinowski Z, Pai EF, Pereira PJ, Petosa C, Raman CS, Rapoport TA, Roll-Mecak A, Rosen MK, Rudenko G, Schlessinger J, Schwartz TU, Shamoo Y, Sondermann H, Tao YJ, Tolia NH, Tsodikov OV, Westover KD, Wu H, Foster I, Fraser JS, Maia FR, Gonen T, Kirchhausen T, Diederichs K, Crosas M, Sliz P (2016) Data publication with the structural biology data grid supports live analysis. Nat Commun 7: 10882 doi: 10.1038/ncomms10882

Matsuyama BY, Krasteva PV, Baraquet C, Harwood CS, Sondermann H, Navarro MV (2016) Mechanistic insights into c-di-GMP-dependent control of the biofilm regulator FleQ from Pseudomonas aeruginosa. Proc Natl Acad Sci U S A 113: E209-218 doi: 10.1073/pnas.1523148113

Dahlstrom KM, Giglio KM, Sondermann H, O'Toole GA (2016) The Inhibitory Site of a Diguanylate Cyclase Is a Necessary Element for Interaction and Signaling with an Effector Protein. J Bacteriol 198: 1595-1603 doi: 10.1128/JB.00090-16

Cooley RB, Smith TJ, Leung W, Tierney V, Borlee BR, O'Toole GA, Sondermann H (2016) Cyclic Di-GMP-Regulated Periplasmic Proteolysis of a Pseudomonas aeruginosa Type Vb Secretion System Substrate. J Bacteriol 198: 66-76 doi: 10.1128/JB.00369-15

Cooley RB, O'Donnell JP, Sondermann H (2016) Coincidence detection and bi-directional transmembrane signaling control a bacterial second messenger receptor. Elife 510.7554/eLife.21848


Dahlstrom KM, Giglio KM, Collins AJ, Sondermann H, O'Toole GA (2015) Contribution of Physical Interactions to Signaling Specificity between a Diguanylate Cyclase and Its Effector. mBio 6: e01978-01915 doi: 10.1128/mBio.01978-15


Gao L, Giglio KM, Nelson JL, Sondermann H, Travis AJ (2014) Ferromagnetic nanoparticles with peroxidase-like activity enhance the cleavage of biological macromolecules for biofilm elimination. Nanoscale 6: 2588-2593 doi: 10.1039/c3nr05422e

Chatterjee D, Cooley RB, Boyd CD, Mehl RA, O'Toole GA, Sondermann H (2014) Mechanistic insight into the conserved allosteric regulation of periplasmic proteolysis by the signaling molecule cyclic-di-GMP. Elife 3: e03650 doi: 10.7554/eLife.03650


McNew JA, Sondermann H, Lee T, Stern M, Brandizzi F (2013) GTP-dependent membrane fusion. Annu Rev Cell Dev Biol 29: 529-550 doi: 10.1146/annurev-cellbio-101512-122328

Giglio KM, Fong JC, Yildiz FH, Sondermann H (2013) Structural basis for biofilm formation via the Vibrio cholerae matrix protein RbmA. J Bacteriol 195: 3277-3286 doi: 10.1128/JB.00374-13

Byrnes LJ, Singh A, Szeto K, Benvin NM, O'Donnell JP, Zipfel WR, Sondermann H (2013) Structural basis for conformational switching and GTP loading of the large G protein atlastin. EMBO J 32: 369-384 doi: 10.1038/emboj.2012.353


Sondermann H, Shikuma NJ, Yildiz FH (2012) You've come a long way: c-di-GMP signaling. Curr Opin Microbiol 15: 140-146 doi: 10.1016/j.mib.2011.12.008

Rozovsky S, Forstner MB, Sondermann H, Groves JT (2012) Single molecule kinetics of ENTH binding to lipid membranes. J Phys Chem B 116: 5122-5131 doi: 10.1021/jp210045r

Krasteva PV, Giglio KM, Sondermann H (2012) Sensing the messenger: the diverse ways that bacteria signal through c-di-GMP. Protein Sci 21: 929-948 doi: 10.1002/pro.2093

Goh SL, Wang Q, Byrnes LJ, Sondermann H (2012) Versatile membrane deformation potential of activated pacsin. PLoS One 7: e51628 doi: 10.1371/journal.pone.0051628

Chatterjee D, Boyd CD, O'Toole GA, Sondermann H (2012) Structural characterization of a conserved, calcium-dependent periplasmic protease from Legionella pneumophila. J Bacteriol 194: 4415-4425 doi: 10.1128/JB.00640-12

Boyd CD, Chatterjee D, Sondermann H, O'Toole GA (2012) LapG, required for modulating biofilm formation by Pseudomonas fluorescens Pf0-1, is a calcium-dependent protease. J Bacteriol 194: 4406-4414 doi: 10.1128/JB.00642-12


Wang Q, Byrnes LJ, Shui B, Rohrig UF, Singh A, Chudakov DM, Lukyanov S, Zipfel WR, Kotlikoff MI, Sondermann H (2011) Molecular mechanism of a green-shifted, pH-dependent red fluorescent protein mKate variant. PLoS One 6: e23513 doi: 10.1371/journal.pone.0023513

Shui B, Wang Q, Lee F, Byrnes LJ, Chudakov DM, Lukyanov SA, Sondermann H, Kotlikoff MI (2011) Circular permutation of red fluorescent proteins. PLoS One 6: e20505 doi: 10.1371/journal.pone.0020505

Newell PD, Boyd CD, Sondermann H, O'Toole GA (2011) A c-di-GMP effector system controls cell adhesion by inside-out signaling and surface protein cleavage. PLoS Biol 9: e1000587 doi: 10.1371/journal.pbio.1000587

Navarro MV, Newell PD, Krasteva PV, Chatterjee D, Madden DR, O'Toole GA, Sondermann H (2011) Structural basis for c-di-GMP-mediated inside-out signaling controlling periplasmic proteolysis. PLoS Biol 9: e1000588 doi: 10.1371/journal.pbio.1000588

Forster BM, Bitar AP, Slepkov ER, Kota KJ, Sondermann H, Marquis H (2011) The metalloprotease of Listeria monocytogenes is regulated by pH. J Bacteriol 193: 5090-5097 doi: 10.1128/JB.05134-11

Byrnes LJ, Sondermann H (2011) Structural basis for the nucleotide-dependent dimerization of the large G protein atlastin-1/SPG3A. Proc Natl Acad Sci USA 108: 2216-2221 doi: 10.1073/pnas.1012792108


Krasteva PV, Fong JC, Shikuma NJ, Beyhan S, Navarro MV, Yildiz FH, Sondermann H (2010) Vibrio cholerae VpsT regulates matrix production and motility by directly sensing cyclic di-GMP. Science 327: 866-868 doi: 10.1126/science.1181185

Gureasko J, Kuchment O, Makino DL, Sondermann H, Bar-Sagi D, Kuriyan J (2010) Role of the histone domain in the autoinhibition and activation of the Ras activator Son of Sevenless. Proc Natl Acad Sci U S A 107: 3430-3435 doi: 10.1073/pnas.0913915107

De N, Navarro MV, Wang Q, Krasteva PV, Sondermann H (2010) Biophysical assays for protein interactions in the Wsp sensory system and biofilm formation. Methods Enzymol 471: 161-184 doi: 10.1016/S0076-6879(10)71010-7


Wang Q, Navarro MV, Peng G, Molinelli E, Goh SL, Judson BL, Rajashankar KR, Sondermann H (2009) Molecular mechanism of membrane constriction and tubulation mediated by the F-BAR protein Pacsin/Syndapin. Proc Natl Acad Sci U S A 106: 12700-12705 doi: 10.1073/pnas.0902974106

Navarro MV, De N, Bae N, Wang Q, Sondermann H (2009) Structural analysis of the GGDEF-EAL domain-containing c-di-GMP receptor FimX. Structure 17: 1104-1116 doi: 10.1016/j.str.2009.06.010

Freedman TS, Sondermann H, Kuchment O, Friedland GD, Kortemme T, Kuriyan J (2009) Differences in flexibility underlie functional differences in the Ras activators son of sevenless and Ras guanine nucleotide releasing factor 1. Structure 17: 41-53 doi: 10.1016/j.str.2008.11.004

De N, Navarro MV, Raghavan RV, Sondermann H (2009) Determinants for the activation and autoinhibition of the diguanylate cyclase response regulator WspR. J Mol Biol 393: 619-633 doi: 10.1016/j.jmb.2009.08.030

Ahmed AH, Wang Q, Sondermann H, Oswald RE (2009) Structure of the S1S2 glutamate binding domain of GLuR3. Proteins 75: 628-637 doi: 10.1002/prot.22274

Ahmed AH, Thompson MD, Fenwick MK, Romero B, Loh AP, Jane DE, Sondermann H, Oswald RE (2009) Mechanisms of antagonism of the GluR2 AMPA receptor: structure and dynamics of the complex of two willardiine antagonists with the glutamate binding domain. Biochemistry 48: 3894-3903 doi: 10.1021/bi900107m


Wang Q, Shui B, Kotlikoff MI, Sondermann H (2008) Structural basis for calcium sensing by GCaMP2. Structure 16: 1817-1827 doi: 10.1016/j.str.2008.10.008

Wang Q, Kaan HY, Hooda RN, Goh SL, Sondermann H (2008) Structure and plasticity of Endophilin and Sorting Nexin 9. Structure 16: 1574-1587 doi: 10.1016/j.str.2008.07.016

Gureasko J, Galush WJ, Boykevisch S, Sondermann H, Bar-Sagi D, Groves JT, Kuriyan J (2008) Membrane-dependent signal integration by the Ras activator Son of sevenless. Nat Struct Mol Biol 15: 452-461 doi: 10.1038/nsmb.1418

De N, Pirruccello M, Krasteva PV, Bae N, Raghavan RV, Sondermann H (2008) Phosphorylation-independent regulation of the diguanylate cyclase WspR. PLoS Biol 6: e67 doi: 10.1371/journal.pbio.0060067


Pirruccello M, Sondermann H, Pelton JG, Pellicena P, Hoelz A, Chernoff J, Wemmer DE, Kuriyan J (2006) A dimeric kinase assembly underlying autophosphorylation in the p21 activated kinases. J Mol Biol 361: 312-326 doi: 10.1016/j.jmb.2006.06.017

Freedman TS, Sondermann H, Friedland GD, Kortemme T, Bar-Sagi D, Marqusee S, Kuriyan J (2006) A Ras-induced conformational switch in the Ras activator Son of sevenless. Proc Natl Acad Sci U S A 103: 16692-16697 doi: 10.1073/pnas.0608127103

Boykevisch S, Zhao C, Sondermann H, Philippidou P, Halegoua S, Kuriyan J, Bar-Sagi D (2006) Regulation of ras signaling dynamics by Sos-mediated positive feedback. Curr Biol 16: 2173-2179 doi: 10.1016/j.cub.2006.09.033


Sondermann H, Zhao C, Bar-Sagi D (2005) Analysis of Ras:RasGEF interactions by phage display and static multi-angle light scattering. Methods 37: 197-202 doi: 10.1016/j.ymeth.2005.05.016

Sondermann H, Nagar B, Bar-Sagi D, Kuriyan J (2005) Computational docking and solution x-ray scattering predict a membrane-interacting role for the histone domain of the Ras activator son of sevenless. Proc Natl Acad Sci U S A 102: 16632-16637 doi: 10.1073/pnas.0508315102

Sondermann H, Kuriyan J (2005) C2 can do it, too. Cell 121: 158-160 doi: 10.1016/j.cell.2005.04.001

Mao X, Ren Z, Parker GN, Sondermann H, Pastorello MA, Wang W, McMurray JS, Demeler B, Darnell JE, Jr., Chen X (2005) Structural bases of unphosphorylated STAT1 association and receptor binding. Mol Cell 17: 761-771 doi: 10.1016/j.molcel.2005.02.021


Sondermann H, Soisson SM, Boykevisch S, Yang SS, Bar-Sagi D, Kuriyan J (2004) Structural analysis of autoinhibition in the Ras activator Son of sevenless. Cell 119: 393-405 doi: 10.1016/j.cell.2004.10.005


Sondermann H, Soisson SM, Bar-Sagi D, Kuriyan J (2003) Tandem histone folds in the structure of the N-terminal segment of the ras activator Son of Sevenless. Structure 11: 1583-1593 doi: 10.1016/j.str.2003.10.015

Margarit SM, Sondermann H, Hall BE, Nagar B, Hoelz A, Pirruccello M, Bar-Sagi D, Kuriyan J (2003) Structural evidence for feedback activation by Ras.GTP of the Ras-specific nucleotide exchange factor SOS. Cell 112: 685-695 doi: 10.1016/s0092-8674(03)00149-1

Harkiolaki M, Lewitzky M, Gilbert RJ, Jones EY, Bourette RP, Mouchiroud G, Sondermann H, Moarefi I, Feller SM (2003) Structural basis for SH3 domain-mediated high-affinity binding between Mona/Gads and SLP-76. EMBO J 22: 2571-2582 doi: 10.1093/emboj/cdg258


Sondermann H, Ho AK, Listenberger LL, Siegers K, Moarefi I, Wente SR, Hartl FU, Young JC (2002) Prediction of novel Bag-1 homologs based on structure/function analysis identifies Snl1p as an Hsp70 co-chaperone in Saccharomyces cerevisiae. J Biol Chem 277: 33220-33227 doi: 10.1074/jbc.M204624200

El Mourabit H, Poinat P, Koster J, Sondermann H, Wixler V, Wegener E, Laplantine E, Geerts D, Georges-Labouesse E, Sonnenberg A, Aumailley M (2002) The PDZ domain of TIP-2/GIPC interacts with the C-terminus of the integrin alpha5 and alpha6 subunits. Matrix Biol 21: 207-214 doi: 10.1016/s0945-053x(01)00198-6


Sondermann H, Scheufler C, Schneider C, Hohfeld J, Hartl FU, Moarefi I (2001) Structure of a Bag/Hsc70 complex: convergent functional evolution of Hsp70 nucleotide exchange factors. Science 291: 1553-1557 doi: 10.1126/science.1057268


Sondermann H, Becker T, Mayhew M, Wieland F, Hartl FU (2000) Characterization of a receptor for heat shock protein 70 on macrophages and monocytes. Biol Chem 381: 1165-1174 doi: 10.1515/BC.2000.144


Sondermann H, Dogic D, Pesch M, Aumailley M (1999) Targeting of cytoskeletal linker proteins to focal adhesion complexes is reduced in fibroblasts adhering to laminin-1 when compared to fibronectin. Cell Adhes Commun 7: 43-56 doi: 10.3109/15419069909034391


Obermann WM, Sondermann H, Russo AA, Pavletich NP, Hartl FU (1998) In vivo function of Hsp90 is dependent on ATP binding and ATP hydrolysis. J Cell Biol 143: 901-910 doi: 10.1083/jcb.143.4.901