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Workgroup Cryo-Electron Microscopy of Macromolecular Machines (Christian Spahn Lab)

The Spahn lab researches:

  • the structure and
  • dynamics of macromolecular machines using three-dimensional cryo-electron microscopy.

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Workgroup Cryo-electron Microscopy of Macromolecular Machines

The main focus of the Spahn lab is the analysis of the structure and dynamics of macromolecular machines using three-dimensional cryo-electron microscopy.

One of the core interests of the Spahn group is the translational apparatus. Protein biosynthesis is a key step during the translation of the genome into the proteome and thus paramount for the living cell. The ribosome, as the central machine of translation, thus constitutes the connection between the nucleic-acid and the amino-acid world. It is itself built from blocks coming from both worlds, comprising both ribosomal RNA and ribosomal proteins.

Translation of the genetic code

At the ribosome, genetic information is translated according to the rules of the genetic code in four distinct phases:

  • Initiation, where the small and the large ribosomal subunits are joined on an mRNA template while selecting an appropriate start codon.
  • Elongation, where the ribosome elongates the nascent polypeptide chain in repetitive cycles of selection of the appropriate tRNA matching the current codon and catalysitic addition of a new amino acid.
  • Termination, where the ribosome halts elongation and protein biosynthesis at defined stop codons.
  • Recycling, where the ribosomal subunits dissociate again, to be free for another cycle.

Translation is governed by a complex regulation mechanism, which is enacted by a multitude of translational factors. These induce conformational changes in the ribosome and fine-tune its structural dynamics. Also cis-acting elements, e.g. viral IRES-RNAs (internal ribosomal entry site), can change the dynamics of the ribosome. The identification of the binding sites at the ribosome and the properties of these interactions, together with understanding the resulting structural changes, thus advances our understanding of the molecular mechanism of protein biosynthesis as well as translational control.
While biologically necessary, the structural flexibility of the ribosome interferes with structure determination. Especially if prepared in vitro, protein complex tend to be structurally heterogeneous. To overcome this obstacle, we have developed various methods to classify the three-dimensional structures and use them to separate individual conformers in silico. This approach not only allows us to determine highly resolved structures of this flexible macromolecular machine, but also to identify the dynamics of structural changes and their biological meaning.