In Nature, structure defines function. Thus, detailed structural information is indispensible to understand the processes that occur on the molecular level inside the cell and that are fundamental to health and disease.
Electron Microscopy (EM) allows us to directly visualize macromolecules that are only a few nanometers large and therefore, to analyze their 3D structure.
The lab uses cryoEM (a method in which the sample can be imaged in the buffer at low temperatures) to determine the structural composition of molecular machines and to analyze the underpinning mechanisms of their function.
The lab analyses the conformational dynamics of membrane proteins that actively move cargo through the lipid bilayer. Membrane transporters are essential to maintain cellular homeostasis or to organize and structure the lipid bilayer.
During transport the protein typically undergoes dramatic conformational changes between an inward and an outward open conformation, using ATP as fuel. If we want to understand how these machines work we need high-resolution structure information and knowledge about their conformational spectrum.
We use cryoEM and tilt-based approaches to obtain such data. Therefore, we routinely employ a method called Random Conical Tilt (RCT, Radermacher 1988) to display the entire conformational spectrum of an actively transporting protein in a single experiment. Subsequently we can analyze this spectrum to decipher the conformational states precisely (also see Moeller et al. 2015). In a sense it is like watching a running engine in slow motion!
Sortilins (or Vps10p-domain receptors) are type-I membrane proteins that are highly expressed in the human brain and are functionally linked to neurodegenerative disorders such as Schizophrenia, Alzheimer’s and Huntington’s disease. Sortilins form the 3rd class of neurotrophic receptors (in addition to Trk and p75NTR) and therefore inhabit crucial roles in modulating synaptic plasticity and neuronal development ( Nykjær & Willnow 2012). They selectively bind to pro-neurotrophins and also act as co-receptor in complex with Trk and p75NTR. Intriguingly, pro-neurotrophins are not exclusive ligands for sortilins. In fact they interact with a large and diverse range of protein ligands, which explains their additional involvement in diabetes, cancer and cardiovascular diseases ( Carlo et al. 2014 ). We want to provide a detailed structural picture on sortilins in complex with protein ligands to understand the underpinning mechanisms of this class of neurotrophic receptors.
Optimal sample preparations are key for successful structure determination. Even the best imaging conditions cannot improve a poorly prepared sample (garbage in, garbage out). Thus, sample optimization is a key step for final success! This is even more important for delicate membrane proteins that require a hydrophobic environment, which mimics the lipid bilayer as closely as possible.
To improve sample quality we are also interested in method development, as highlighted by the invention of a novel form of peptide detergents. These short peptides (8aa) significantly enhance the stability of membrane proteins and provide a close to native environment ( Tao et al. 2013).
We also routinely use high-throughput EM analysis to screen and optimize samples on their way towards an ideal preparation (see for example Kang et al. 2015).
Since Dec. 2015 Arne is an Independent Group Leader at the MPI Biophysics (Frankfurt) in the Department of Structural Biology (Prof. Werner Kühlbrandt).
Initially he started his own group as Principal Investigator at Aarhus University (AU), the Danish Research Institute of Translational Neuroscience (DANDRITE) and the interdisciplinary Nanoscience center (iNANO) in 2014. At AU he established a cryoEM facility including a Titan Krios TEM and disseminated the technology to prepare and image samples and process the acquired data. Arne retains close contacts with AU as affiliated researcher.
For his PostDoc Arne moved to Southern California to work in the lab of Profs. Bridget Carragher and Clinton Potter at the National Resource for Automated Molecular Microscopy (NRAMM), The Scripps Research Institute (TSRI) La Jolla, CA. At TSRI he was involved in the Joint Center for Innovative Membrane Protein Technologies (JCIMPT), led by Prof. Ray Stevens.
During his PostDoc he worked on multiple projects including both methods development and structural studies.
Arne obtained his Doctorates Degree from the Johannes-Gutenberg University Mainz (JGU) (group of Prof. Jürgen Markl).
He performed structural studies on the gigantic, extracellular oxygen carriers (hemocyanins) from mollusks and arthropods and their conformational changes during oxygen uptake/release.
Dr. Arne Möller
Independent Research Group Leader
Affiliated Researcher DANDRITE
Department of Structural Biology
Max-Planck-Institute of Biophysics
D-60438 Frankfurt am Main
Arne.Moeller at biophys.mpg.de
Dovile obtained her PhD degree in February 2015 from the University of Aarhus, Denmark (AU). As a PhD student she was working in the group of Prof. Søren Skou Thirup at the Center for Structural Biology and was associated with the Membrane Receptors in Neuronal Disease center (MIND). During her PhD Dovile performed structural studies on mammalian neuronal receptors.
Moritz started in the lab in June 2016 as a Master student from the Technical University of Darmstadt (TUD). His projects involve the structural characterization of human SorCS1 by cryoEM, as well as cryoEM method development.
Theresa is a Master student from the Ruhr-University Bochum working on the “death complex”. For her Bachelor thesis she performed structural studies and biochemical analyses of different bacterial cell division proteins.
Anne studies biochemistry in her masters at the university of Tübingen. As a part of that, she does an internship in our lab. Here, she works on sortilin and SorCS1 nanobodies to facilitate EM analyses of both proteins. She did her bachelor thesis in Prof. Thilo Stehles lab at the Interfaculty Institute for Biochemistry in Tübingen, where she structurally analyzed a virus capsid protein by Xray crystallography.
Recent technical break-throughs in the field of single particle cryo electron microscopy now allow 3D reconstructions of protein complexes at near-atomic resolution, provided they are over ~100 kDa. This size limit excludes structure determination of many small but important protein targets. In a strong collaboration, the Geertsma (Goethe university) and Möller (MPI for Biophysics) aim to bring this practical limit closer to the theoretical size limit of 20-40 kDa using state of the art protein engineering and image processing algorithms. Interested? Contact Arne Möller or Eric Geertsma.
We have several interesting projects for Master/Bachelor level students available and are looking for highly motivated candidates. If you want to elucidate the 3D structure of membrane proteins using cutting edge Electron Microscopy technology please contact Arne Moeller directly!
Currently there are no open positions for Grad. Students available in the lab. However, students with external funding are welcome to join!
Currently there are no open PostDoc positions in the lab. However, PhDs with external funding are welcome to join!