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Carsten Sachse

Autophagy (from the Greek, meaning ‘to eat oneself’) is the cell’s housekeeping mechanism to engulf and degrade long-lived proteins, macromolecular aggregates, damaged organelles and even microbes in double-membrane vesicles called autophagosomes.

In our group, we investigate the molecular structures involved in autophagy as they provide fundamental insights for our understanding of aberrant cellular processes like cancer, ageing or infection.

AutophagyCopyright: 2018 Carsten Sachse

Multiprotein complexes are essential mediators in the events leading to autophagy. On the structural level, however, little is known about their 3D architecture. Fundamental questions on the nature of these complexes need to be addressed:

  • How are protein deposits structurally linked to autophagy?
  • What are the shapes of these multiprotein assemblies at the membrane?
  • How do they give rise to the cellular structure of the autophagosome?

Electron cryomicroscopy is a powerful structural biology technique

We study the structures of molecular assemblies using biochemical and biophysical techniques, and subsequently visualise them by electron cryomicroscopy (cryo-EM). By this technique, large macromolecular structures and multi-protein complexes can be studied in their near-native environment without the need for crystalisation. Small amounts of material are sufficient to obtain ‘snapshots’ of single particles in the electron cryomicroscope. The molecular images are combined by computer-aided image processing techniques to compute their 3D structures. As recent advances in hardware and software have led to a wave of atomic-resolution structures, cryo-EM shows great promise in becoming a routine tool for high-resolution structure determination of large macromolecules. To further realise the potential of the technique, the scientific community is still in great need of hardware-based improvements and software enhancements. Therefore, we are also interested in developing techniques, including sample preparation and data processing, to routinely achieve atomic-resolution structures by single-particle cryo-EM. For example, in our group we actively develop the software SPRING for high-resolution cryo-EM structure determination of specimens with helical symmetry.

HelixClose-up of a-helix including sidechain density.
Copyright: 2018 Carsten Sachse

Electron cryomicroscopyHigh-resolution cross section of tobacco mosaic virus at 3.3 Å resolution using single-particle cryo-EM from direct electron detectors including  α-helical density (Fromm et al., J Struc Biol 2015).
Copyright: 2018 Carsten Sachse

Method development

  • Spring
  • Helical diffraction simulator
  • LocScale

Spring is a single-particle based helical reconstruction package developed in our laboratory to determine 3D structures of a variety of highly ordered and less ordered specimens with helical symmetry from electron micrographs.

SpringCopyright: 2018 Carsten Sachse

Helical diffraction simulator is a web server tool developed in our laboratory to display Fourier patterns of helices based on input helical symmetry parameters according to the theory formulated by Cochran, Crick and Vand in 1952.

Helical_diffraction_simulationCopyright: Carsten Sachse 2018

LocScale is density scaling (sharpening) procedure that aims to enhance interpretability of cryo-EM density maps. LocScale is a reference-based local amplitude scaling tool using prior model information to improve contrast of cryo-EM density maps.

LocScaleCopyright: Carsten Sachse 2018