Research Profile Dr. Arne Möller

Arne Möller
  • Dr. rer. nat., JGU Mainz, Germany, 2009
  • Postdoc, The Scripps Research Institute, La Jolla, CA, United States 2009 - 2014
  • Assistant Prof., interdisciplinary Nano Science Center, Aarhus University, Aarhus Denmark, 2014 - 2015
  • Team Leader, The Danish Research Institute of Translational Neuroscience , Aarhus University, Aarhus Denmark, 2014 - 2015
  • Affiliated Researcher, The Danish Research Institute of Translational Neuroscience , Aarhus University, Aarhus Denmark,  since Dec. 2015
  • Independent research group leader, since Dec. 2015

    A direct view on macromolecular machines

    The lab uses cryoEM to characterize 3D structures of membrane proteins. We set our focus on the analysis of the dynamics of trans-membrane transporters that actively translocate substrates through the lipid bilayer and neuronal surface receptors that are involved in trafficking and signaling.

    We are also pursuing methods development to improve EM-imaging and optimize the sample.

    Approach: An EM image is an immediate representation of the sample and allows to directly visualize individual macromolecular complexes at great detail. We utilize this unique feature in structural biology to assess the conformational spectrum of membrane proteins.

    Therefore, an EM-imaging pipeline and standardized, streamlined workflows were established. This setup allows us to automatically record and analyze datasets of ~10-20 different samples in day, at room temperature. Sophisticated algorithms group the different conformations into homogenous classes and 3D analysis can be applied to obtain structures of the discrete states. This pipeline can also be used during optimization and quality assessment of the sample.

    Figure 2.
    Figure 1. ABC transporters are well known to undergo significant conformational changes during ATP-hydrolysis and substrate translocation. In our EM-study we were able to represent the entire conformational spectrum of two homologous ABC transporters and to identify marked differences.

    Transporter: 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 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. In a sense it is like watching a running engine in slow motion!

    Figure 1. The F1Fo-ATP synthase, a paradigmatic molecular machine. Schematic representation of the subunit organization. The F1 domain, with the three catalytic sites on the three β-subunits (light green), is connected via the γ and ε subunits (blue, central stalk) to the c-oligomer (blue, in the membrane) of the Fo domain, and via the outer stalk δ (orange) and b2 (yellow) subunits to subunit a (red). Mechanistically the enzyme can be divided into the rotor, which consists of subunits c8-15γε (in blue), and the stator, assembled by subunits ab2α3β3δ (green and orange/yellow). The ions are shown as yellow spheres on their pathway through the Fo complex. The figure was created by Paolo Lastrico (Max-Planck-Institute of Biophysics, Graphics).
    Figure 2. Artistic representation of the members of the Sortilin family. Currently only small, isolated fragments are described. Full-length structures at high-resolution are required to describe how Sortilins can interact with their many binding-partners and how this triggers different signaling pathways

    Neuroreceptors: 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. 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. 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.

    Figure 3.
    Figure 3. Beta-peptides protect membrane proteins. Beta-barrel proteins are extremely stable. We hypothesized that if membrane proteins can be encapsulated by a beta-barrel its stability would also be transferred. Therefore, we engineered small peptides that confer facial amphilicity and enable hydrogen bonding between neighboring strands. Our design significantly increased the stability of the three main classes of membrane proteins: Transporter, Receptors and Channels.

    Methods: 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.

    We also routinely use high-throughput EM analysis to screen and optimize samples on their way towards an ideal preparation.

    Publications - (2007 - present)

    * Co-first author
    + Highlighted on the cover of the magazine

    2015
    Kang, et al. (2015). Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser. Nature .

    Moeller*, Lee*, et al. (2015). Distinct Conformational Spectrum of Homologous Multidrug ABC Transporters. Structure

    Leung, Schurig-Briccio, Yamaguchi, Moeller, et al. (2015). Division of labor in transhydrogenase by alternating proton translocation and hydride transfer. Science

    Yang, Yang, de Graaf, Moeller, et al (2015). Conformational states of the full-length glucagon receptor. Nat. Commun.

    Ye, Rosenberg, Moeller, et al. (2015). TRIP13 is a protein-remodeling AAA+ ATPase that catalyzes MAD2 conformation switching. Elife

    2014
    Bhabha, Cheng, Zhang, Moeller , et al. (2014). Allosteric communication in the dynein motor domain. Cell

    2013
    Tao*, Lee*, Moeller* (co-first author), et al. (2013). Engineered nanostructured β-sheet peptides protect membrane proteins. Nat. Methods selected by F-1000.

    2012
    Moeller*
    , Kirchdoerfer*, et al. (2012). Organization of the influenza virus replication machinery. Science 77 citations

    + Campbell*, Cheng*, Brilot, Moeller, et al. (2012). Movies of ice-embedded particles enhance resolution in electron cryo-microscopy. Structure 90 citations

    Moeller, et al. (2012). Nucleotide-dependent conformational changes in the N-Ethylmaleimide Sensitive Factor (NSF) and their potential role in SNARE complex disassembly. J. Struct. Biol.

    Xu*, Moeller* (co-first author), et al. (2012). Assembly and channel opening of outer membrane protein in tripartite drug efflux pumps of Gram-negative bacteria. J. Biol. Chem.

    2011
    Milazzo, Cheng, Moeller, et al. (2011). Initial evaluation of a direct detection device detector for single particle cryo-electron microscopy. J. Struct. Biol. 41 citations

    Xu, Lee, Moeller, et al. (2011). Funnel-like hexameric assembly of the periplasmic adapter protein in the tripartite multidrug efflux pump in gram-negative bacteria. J. Biol. Chem.

    Xu, Song, Moeller, et al. (2011). Functional implications of an intermeshing cogwheel-like interaction between TolC and MacA in the action of macrolide-specific efflux pump MacAB-TolC. J. Biol. Chem.

    Moeller, Dürr, Sarraf-Zadeh, Keller, Heinz, Hellmann, Moeller, et al. (2011). Recombinant functional multidomain hemoglobin from the gastropod Biomphalaria glabrata. IUBMB Life

    2010
    Lyumkis, Moeller, et al. (2010). Chapter Fourteen-Automation in Single-Particle Electron Microscopy: Connecting the Pieces. Methods Enzymol. 2009 Markl, Moeller, et al. (2009). 10Å cryoEM structure and molecular model of the myriapod (Scutigera) 6 times 6mer hemocyanin: understanding a giant oxygen transport protein. J. Mol. Biol.

    2007
    Gatsogiannis, Moeller, et al. (2007). Nautilus pompilius Hemocyanin: 9 Å Cryo-EM Structure and Molecular Model Reveal the Subunit Pathway and the Interfaces between the 70 Functional Units. J. Mol. Biol.

    Meissner, Gatsogiannis, Moeller, et al. (2007). Comparative 11A structure of two molluscan hemocyanins from 3D cryo-electron microscopy. Micron

    Contact:

    Max Planck Institute of Biophysics

    Dr. Arne Möller
    Department of Structural Biology

    Phone: +49 (0) 69 6303-3038
    Fax: +49 (0) 69 6303-3002
    E-mail:arne.moeller(at)biophys.mpg.de

    Möller - Group Members:

    Group Leader:

    PhD Students:

    Research assistant:

    • Luise Eckhardt-Strelau

    Students:

    Flyer Master/Dipl. Students