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David Haselbach

Cells are factories full of molecular machines, fuelled by the thermal energy of the surrounding medium. Randomly impacting solution molecules force the machines to vibrate and therefore move in all directions. Only through well-placed structural features, that prohibit some of the random movements, can molecules work productively. Our lab aims to identify and understand design principles of molecular machines. We use biophysical techniques – in particular cryo-electron microscopy – to watch them in action.

Publications

2025

Harar, P., Herrmann, L., Grohs, P., Haselbach, D. (2025)

FakET: Simulating cryo-electron tomograms with neural style transfer.

 Structure.
Rudi, O., Hodakova, Z., Farias Saad, C., Winter, N., Grishkovskaya, I., Böhm, J., Jarck, G., Schleiffer, A., Haselbach, D., Bachmair, A. (2025)

The UBR Domain of Plant Ubr1 Homolog PRT6 Accommodates Basic and Hydrophobic Amino Termini for Substrate Recognition.

 J Mol Biol. 437(4):168939

2024

Pre-printBrunner HL, Kalis RW, Grundmann L, Hodáková Z, Koskova Z, Grishkovskaya I, de Almeida M, Hinterndorfer M, Höfflin S, Andersch F, Kotisch H, Dickmanns A, Cuylen-Häring S, Zuber J, Haselbach D (2024)

A multivalent adaptor mechanism drives the nuclear import of proteasomes

 bioRxiv. 2024.11.08.622636
Pre-printDe La Concepcion JC, Duverge H, Kim Y, Julian J, Xu HD, Ikene SA, Bianchi A, Grujic N, Papareddy RK, Grishkovskaya I, Haselbach D, Murray DH, Clavel M , Irwin NAT, Dagdas Y (2024)

Electrostatic changes enabled the diversification of an exocyst subunit via protein complex escape

bioRxiv. 2024.08.26.609756
Kofler, L., Grundmann, L., Gerhalter, M., Prattes, M., Merl-Pham, J., Zisser, G., Grishkovskaya, I., Hodirnau, VV., Vareka, M., Breinbauer, R., Hauck, SM., Haselbach, D., Bergler, H. (2024)

The novel ribosome biogenesis inhibitor usnic acid blocks nucleolar pre-60S maturation.

 Nat Commun. 15(1):7511
Pre-printLambrecht F, Kröpelin A, Lüttich M, Habeck M, Haselbach D, Stark H (2024)

CowScape: Quantitative reconstruction of the conformational landscape of biological macromolecules from cryo-EM data

 arXiv. 2402.11589
Pre-printSchwartz I, Budroni V, Meyenberg M, Hornegger H, Hacker K, Schwartz S, Hodakova Z, Grabarczyk DB, Ehrmann JF , Scinicariello S, Haselbach D, Menche J, Clausen T, Karagöz E, Versteeg GA (2024)

Guardian ubiquitin E3 ligases target cancer-associated APOBEC3 deaminases for degradation to promote human genome integrity

bioRxiv. 2024.04.23.590688
Pre-printShah, AN., Leesch, F., Lorenzo-Orts, L., Grundmann, L., Novatchkova, M., Haselbach, D., Calo, E., Pauli, A. (2024)

A dual ribosomal system in the zebrafish soma and germline

 bioRxiv. doi:10.1101/2024.08.29.610041
Shah, AN., Leesch, F., Lorenzo-Orts, L., Grundmann, L., Novatchkova, M., Haselbach, D., Calo, E., Pauli, A. (2024)

A dual ribosomal system in the zebrafish soma and germline.

 bioRxiv.

2023

Amann, SJ., Keihsler, D., Bodrug, T., Brown, NG., Haselbach, D. (2023)

Frozen in time: analyzing molecular dynamics with time-resolved cryo-EM.

 Structure. 31(1):4-19
Bodrug, T., Welsh, KA., Bolhuis, DL., Paulаkonis, E., Martinez-Chacin, RC., Liu, B., Pinkin, N., Bonacci, T., Cui, L., Xu, P., Roscow, O., Amann, SJ., Grishkovskaya, I., Emanuele, MJ., Harrison, JS., Steimel, JP., Hahn, KM., Zhang, W., Zhong, ED., Haselbach, D., Brown, NG. (2023)

Time-resolved cryo-EM (TR-EM) analysis of substrate polyubiquitination by the RING E3 anaphase-promoting complex/cyclosome (APC/C).

 Nat Struct Mol Biol. 30(11):1663-1674
Hodáková, Z., Grishkovskaya, I., Brunner, HL., Bolhuis, DL., Belačić, K., Schleiffer, A., Kotisch, H., Brown, NG., Haselbach, D. (2023)

Cryo-EM structure of the chain-elongating E3 ubiquitin ligase UBR5.

 EMBO J. 42(16):e113348
Leesch, F., Lorenzo-Orts, L., Pribitzer, C., Grishkovskaya, I., Roehsner, J., Chugunova, A., Matzinger, M., Roitinger, E., Belačić, K., Kandolf, S., Lin, TY., Mechtler, K., Meinhart, A., Haselbach, D., Pauli, A. (2023)

A molecular network of conserved factors keeps ribosomes dormant in the egg.

Corresponding preprint Nature.

2022

Kandolf, S., Grishkovskaya, I., Belačić, K., Bolhuis, DL., Amann, S., Foster, B., Imre, R., Mechtler, K., Schleiffer, A., Tagare, HD., Zhong, ED., Meinhart, A., Brown, NG., Haselbach, D. (2022)

Cryo-EM structure of the plant 26S proteasome.

 Plant Commun. 3(3):100310
Morreale, FE., Kleine, S., Leodolter, J., Junker, S., Hoi, DM., Ovchinnikov, S., Okun, A., Kley, J., Kurzbauer, R., Junk, L., Guha, S., Podlesainski, D., Kazmaier, U., Boehmelt, G., Weinstabl, H., Rumpel, K., Schmiedel, VM., Hartl, M., Haselbach, D., Meinhart, A., Kaiser, M., Clausen, T. (2022)

BacPROTACs mediate targeted protein degradation in bacteria.

Corresponding preprint Cell. 185(13):2338-2353.e18
Pechincha, C., Groessl, S., Kalis, R., de Almeida, M., Zanotti, A., Wittmann, M., Schneider, M., de Campos, RP., Rieser, S., Brandstetter, M., Schleiffer, A., Müller-Decker, K., Helm, D., Jabs, S., Haselbach, D., Lemberg, MK., Zuber, J., Palm, W. (2022)

Lysosomal enzyme trafficking factor LYSET enables nutritional usage of extracellular proteins.

 Science. 378(6615):eabn5637
Prattes, M., Grishkovskaya, I., Hodirnau, VV., Hetzmannseder, C., Zisser, G., Sailer, C., Kargas, V., Loibl, M., Gerhalter, M., Kofler, L., Warren, AJ., Stengel, F., Haselbach, D., Bergler, H. (2022)

Visualizing maturation factor extraction from the nascent ribosome by the AAA-ATPase Drg1.

 Nat Struct Mol Biol. 29(9):942-953

2021

de Almeida, M., Hinterndorfer, M., Brunner, H., Grishkovskaya, I., Singh, K., Schleiffer, A., Jude, J., Deswal, S., Kalis, R., Vunjak, M., Lendl, T., Imre, R., Roitinger, E., Neumann, T., Kandolf, S., Schutzbier, M., Mechtler, K., Versteeg, GA., Haselbach, D., Zuber, J. (2021)

AKIRIN2 controls the nuclear import of proteasomes in vertebrates.

 Nature. 599(7885):491-496
Grabarczyk, DB., Petrova, OA., Deszcz, L., Kurzbauer, R., Murphy, P., Ahel, J., Vogel, A., Gogova, R., Faas, V., Kordic, D., Schleiffer, A., Meinhart, A., Imre, R., Lehner, A., Neuhold, J., Bader, G., Stolt-Bergner, P., Böttcher, J., Wolkerstorfer, B., Fischer, G., Grishkovskaya, I., Haselbach, D., Kessler, D., Clausen, T. (2021)

HUWE1 employs a giant substrate-binding ring to feed and regulate its HECT E3 domain.

 Nat Chem Biol.
Gutiérrez-Pérez, P., Santillán, EM., Lendl, T., Wang, J., Schrempf, A., Steinacker, TL., Asparuhova, M., Brandstetter, M., Haselbach, D., Cochella, L. (2021)

miR-1 sustains muscle physiology by controlling V-ATPase complex assembly.

 Sci Adv. 7(42):eabh1434
Prattes, M., Grishkovskaya, I., Hodirnau, VV., Rössler, I., Klein, I., Hetzmannseder, C., Zisser, G., Gruber, CC., Gruber, K., Haselbach, D., Bergler, H. (2021)

Structural basis for inhibition of the AAA-ATPase Drg1 by diazaborine.

 Nat Commun. 12(1):3483
Rodriguez Carvajal, A., Grishkovskaya, I., Gomez Diaz, C., Vogel, A., Sonn-Segev, A., Kushwah, MS., Schodl, K., Deszcz, L., Orban-Nemeth, Z., Sakamoto, S., Mechtler, K., Kukura, P., Clausen, T., Haselbach, D., Ikeda, F. (2021)

The linear ubiquitin chain assembly complex (LUBAC) generates heterotypic ubiquitin chains.

Corresponding preprint Elife. 10
Schimpf, J., Oppermann, S., Gerasimova, T., Santos Seica, AF., Hellwig, P., Grishkovskaya, I., Wohlwend, D., Haselbach, D., Friedrich, T. (2021)

Structure of the peripheral arm of a minimalistic respiratory complex I.

 Structure.

2020

Ahel, J., Lehner, A., Vogel, A., Schleiffer, A., Meinhart, A., Haselbach, D., Clausen, T. (2020)

Moyamoya disease factor RNF213 is a giant E3 ligase with a dynein-like core and a distinct ubiquitin-transfer mechanism.

 Elife. 9
Sonn-Segev, A., Belacic, K., Bodrug, T., Young, G., VanderLinden, RT., Schulman, BA., Schimpf, J., Friedrich, T., Dip, PV., Schwartz, TU., Bauer, B., Peters, JM., Struwe, WB., Benesch, JLP., Brown, NG., Haselbach, D., Kukura, P. (2020)

Quantifying the heterogeneity of macromolecular machines by mass photometry.

 Nat Commun. 11(1):1772

2019

Prajapati, S., Haselbach, D., Wittig, S., Patel, MS., Chari, A., Schmidt, C., Stark, H., Tittmann, K. (2019)

Structural and Functional Analyses of the Human PDH Complex Suggest a "Division-of-Labor" Mechanism by Local E1 and E3 Clusters.

 Structure. 27(7):1124-1136.e4
Watson, ER., Grace, CRR., Zhang, W., Miller, DJ., Davidson, IF., Prabu, JR., Yu, S., Bolhuis, DL., Kulko, ET., Vollrath, R., Haselbach, D., Stark, H., Peters, JM., Brown, NG., Sidhu, SS., Schulman, BA. (2019)

Protein engineering of a ubiquitin-variant inhibitor of APC/C identifies a cryptic K48 ubiquitin chain binding site.

 Proc Natl Acad Sci U S A. 116(35):17280-17289

2018

Haselbach, D., Komarov, I., Agafonov, DE., Hartmuth, K., Graf, B., Dybkov, O., Urlaub, H., Kastner, B., Lührmann, R., Stark, H. (2018)

Structure and Conformational Dynamics of the Human Spliceosomal Bact Complex.

 Cell. 172(3):454-464.e11

2017

Bertram, K., Agafonov, DE., Dybkov, O., Haselbach, D., Leelaram, MN., Will, CL., Urlaub, H., Kastner, B., Lührmann, R., Stark, H. (2017)

Cryo-EM Structure of a Pre-catalytic Human Spliceosome Primed for Activation.

 Cell. 170(4):701-713.e11
Haselbach, D., Schrader, J., Lambrecht, F., Henneberg, F., Chari, A., Stark, H. (2017)

Long-range allosteric regulation of the human 26S proteasome by 20S proteasome-targeting cancer drugs.

 Nat Commun. 8:15578

2016

Brown, NG., VanderLinden, R., Watson, ER., Weissmann, F., Ordureau, A., Wu, KP., Zhang, W., Yu, S., Mercredi, PY., Harrison, JS., Davidson, IF., Qiao, R., Lu, Y., Dube, P., Brunner, MR., Grace, CRR., Miller, DJ., Haselbach, D., Jarvis, MA., Yamaguchi, M., Yanishevski, D., Petzold, G., Sidhu, SS., Kuhlman, B., Kirschner, MW., Harper, JW., Peters, JM., Stark, H., Schulman, BA. (2016)

Dual RING E3 Architectures Regulate Multiubiquitination and Ubiquitin Chain Elongation by APC/C.

 Cell. 165(6):1440-1453
Qiao, R., Weissmann, F., Yamaguchi, M., Brown, NG., VanderLinden, R., Imre, R., Jarvis, MA., Brunner, MR., Davidson, IF., Litos, G., Haselbach, D., Mechtler, K., Stark, H., Schulman, BA., Peters, JM. (2016)

Mechanism of APC/CCDC20 activation by mitotic phosphorylation.

 Proc Natl Acad Sci U S A. 113(19):E2570-8
Yamaguchi, M., VanderLinden, R., Weissmann, F., Qiao, R., Dube, P., Brown, NG., Haselbach, D., Zhang, W., Sidhu, SS., Peters, JM., Stark, H., Schulman, BA. (2016)

Cryo-EM of Mitotic Checkpoint Complex-Bound APC/C Reveals Reciprocal and Conformational Regulation of Ubiquitin Ligation.

 Mol Cell. 63(4):593-607

2015

Chari, A., Haselbach, D., Kirves, JM., Ohmer, J., Paknia, E., Fischer, N., Ganichkin, O., Möller, V., Frye, JJ., Petzold, G., Jarvis, M., Tietzel, M., Grimm, C., Peters, JM., Schulman, BA., Tittmann, K., Markl, J., Fischer, U., Stark, H. (2015)

ProteoPlex: stability optimization of macromolecular complexes by sparse-matrix screening of chemical space.

 Nat Methods. 12(9):859-65

2013

Dölker, N., Blanchet, CE., Voß, B., Haselbach, D., Kappel, C., Monecke, T., Svergun, DI., Stark, H., Ficner, R., Zachariae, U., Grubmüller, H., Dickmanns, A. (2013)

Structural determinants and mechanism of mammalian CRM1 allostery.

 Structure. 21(8):1350-60
Monecke, T., Haselbach, D., Voß, B., Russek, A., Neumann, P., Thomson, E., Hurt, E., Zachariae, U., Stark, H., Grubmüller, H., Dickmanns, A., Ficner, R. (2013)

Structural basis for cooperativity of CRM1 export complex formation.

 Proc Natl Acad Sci U S A. 110(3):960-5

2011

Köster, DM., Haselbach, D., Lehrach, H., Seitz, H. (2011)

A DNAzyme based label-free detection system for miniaturized assays.

 Mol Biosyst. 7(10):2882-9