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Kay Grünewald

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Structural Cell Biology of Viruses

“Research at CSSB will take an integrative structural biology approach, combining results from a broad spectrum of cutting edge imaging technologies and methods, covering a wide range of resolution scales – typically atoms to cells – allowing us to understand infection processes mechanistically. Crucially, information on the spatial resolution will be combined with analysis of the dynamics of the molecular interaction networks during infections, together providing a more complete picture of host-pathogen interactions and defining their common principles.”

Kay Grünewald, CSSB Group Leader

Previous and current research

Cells constitute the smallest autonomous units of life. Supramolecular complexes carry out essentially all functions and processes and form the cells structural elements. The tightly regulated structural and functional organization of a cell at this level is currently only rudimentary understood. A comprehensive analysis of this organization and its dynamic changes requires tools that allow for studying these complexes in their native environment. We apply electron cryo tomography (cryoET) in combination with other techniques to approach selected aspects of this highly ordered network analyzing protein complexes in situ. Sample preparation by fast vitrification, i.e. embedding in amorphous ice, ensures excellent preservation of structure down to the atomic level.

We have pioneered the application of cryoET to isolated pleomorphic viruses revealing their three-dimensional supramolecular organization. Examples are virus particle structures for Herpes simplex virus, HIV-1 and Bunyaviruses. We next concentrated on the cell biology of virus infection. Understanding the entirety of a virus’ ‘life cycle’ requires an understanding of its transient structures at the molecular level. The aim is a comprehensive picture of the functional interaction between viral protein complexes and cellular structures in the course of the infection. Viruses also serve as dedicated tools to mine the molecular detail of cellular tomograms. Being able to enter cells via physiological pathways and being recognizable among the multitude of other structural features inside the hosts cytoplasm, viruses allow for following dynamic cellular processes.

Electron cryo microscopy provides an excellent platform for interfacing with other approaches, like biochemical and X-ray crystallographic studies, and the integration of those inputs with native sub-cellular structural information. Driven by our biological questions we are involved in various efforts of methods development including the combination of cellular and molecular cryoET with ‘single particle’ approaches, advanced fluorescence (cryo) microscopy and soft X-ray cryo microscopy/tomography in a correlative fashion, but also in integrating better with protein-protein-interaction data (e.g. from mass spectrometry) and molecular dynamics simulations.

Publications

Baker L.A., et al. (2018) Combined 1H-Detected Solid-State NMR Spectroscopy and Electron Cryotomography to Study Membrane Proteins across Resolutions in Native Environments. Structure; 26(1):161-170.e3

Baker L.A., et al. (2017) Electron cryo-tomography captures macromolecular complexes in native environments. Curr Opin Struct Biol; 46:149-156

Patwardhan A., et al. (2017) Building bridges between cellular and molecular structural biology. Elife; e25835

Clare D.K., et al. (2017) Electron Bio-Imaging Centre (eBIC): the UK national research facility for biological electron microscopy. Acta Crystallogr D Struct Biol; 73(Pt 6):488-495

Montespan C., et al. (2017) Multi-layered control of Galectin-8 mediated autophagy during adenovirus cell entry through a conserved PPxY motif in the viral capsid. PLoS Pathog; 13(2):e1006217

Riedel C., et al. (2017) Native structure of a retroviral envelope protein and its conformational change upon interaction with the target cell. J Struct Biol; 197(2):172-180

Grange M., et al. (2017) Cellular electron cryo tomography and in situ sub-volume averaging reveal the context of microtubule-based processes. J Struct Biol; 197(2):181-190

Stoeber M., et al. (2016) Model for the architecture of caveolae based on a flexible, net-like assembly of Cavin1 and Caveolin discs. PNAS; 113(50): E8069-E8078

Ashford P., et al. (2016) HVint: A strategy for identifying novel protein-protein interactions in herpes simplex virus type 1. Mol Cell Proteomics; 15(9): 2939-53

Zeev-Ben-Mordehai T., et al. (2016) Two distinct trimeric conformations of natively membrane-anchored full-length herpes simplex virus 1 glycoprotein B. PNAS; 113(15): 4176-81

Zeev-Ben-Mordehai T., et al. (2015) Crystal Structure of the Herpesvirus Nuclear Egress Complex Provides Insights into Inner Nuclear Membrane Remodeling. Cell Rep.; 13(12): 2645-52

Hagen C., et al. (2015) Structural Basis of Vesicle Formation at the Inner Nuclear Membrane. Cell; 163(7): 1692-701



Picture: © Marta Mayer
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