cluster of excellence frankfurt macromolecular complexes


  • Example include light-switchable molecules designed for in-cell applications and time-resolved techniques to study RNA folding.

  • CEF scientists have done groundbreaking work to overcome some of these challenges and made major contributions to elucidating the structure, mechanisms and regulation of a
    number of important large complexes, including respiratory complex I,[3][4] rotary ATPases,[5][6][7][8] Antigenic peptide recognition on TAP was resolved by DNP-enhanced solid-state NMR spectroscopy.

  • Especially solid-state (MAS) NMR enables bridging the gap between ‘static’ structures and biochemical data by probing membrane proteins directly within the bilayer environment.

  • CEF Research Area A – Structure, mechanisms and dynamics of complexes in the membrane[edit] Biological membranes have a very important role in life processes as everything
    a cell needs to live, grow and respond has to either pass through or act on them.

  • CEF grew out of the long-standing collaborative research on membrane proteins and RNA molecules and strengthened research efforts in these fields by recruiting further scientists
    to Frankfurt/Main.

  • Aims CEF scientists set out to investigate the structure and function of large macromolecular complexes, in particular membrane proteins and their assemblies, complexes involved
    in signal transduction and quality control, and RNA-protein complexes.

  • [27][28][29] CEF researchers have developed mass spectrometry approaches specifically suitable for large membrane protein complexes.

  • [1][2] The five research areas of CEF included: (A) Structure, mechanisms and dynamics of complexes in the membrane, (B) Composition and dynamics of macromolecular complexes
    in quality control and signalling, (C) Dynamics of ribonucleic acid-protein-complexes, (D) Design of macromolecular complexes, and (E) Methods for studying macromolecular complexes.

  • [23] The progress in 3D structure determination of membrane proteins by X-ray crystallography and cryo electron microscopy has created an increasing demand and opportunity
    for in-depth mechanistic studies by magnetic resonance methods.

  • Due to the challenges intrinsic to membrane proteins, progress relies on the availability of techniques at the forefront of method development.

  • For example, fundamental contributions were made towards the structural and functional description of proteorhodopsin, a pentameric light-driven proton pump by groups within

  • [30] A team of CEF scientists resolved the mechanism of the subtype selectivity of human bradykinin receptors for their peptide agonists by integrating DNP-enhanced solid-state
    nuclear magnetic resonance with advanced molecular modeling and docking[31]

  • In the crowded conditions of the cell membrane, most membrane proteins associate into complex dynamic assemblies to carry out their various tasks.

  • Several groups of CEF have contributed to advances in understanding how ubiquitin signalling is not only used as a degradation signal but also involved in several other cellular
    processes p63[edit] Research on TP63, also known as p63, has shown that this protein plays essential roles both for the proliferation and differentiation of stratified epithelial tissues as well as for the surveillance of the genetic quality
    in female germ cells.

  • A particular focus of research in CEF has been on protein quality control mechanisms that are the basis for the autophagic and the ubiquitin/proteasomal pathways, the two
    cellular systems used to degrade faulty or superfluous proteins, complexes and organelles.

  • [58] CEF Research Area C – Dynamics of ribonucleic acid-protein-complexes[edit] Many discoveries including the identification of multiple classes of noncoding RNAs and regulatory
    RNA elements has broadened the perspective on RNA function from a passive carrier of information to an active cellular component.

  • A set of probes has been characterized and validated as tools for specific bromodomains[55] Interactions with soluble domains at the membrane[edit] CEF showed that vascular
    endothelial growth factor receptor-2 needs to be internalized and is regulated by its association to ephrin B2 in endothelial cells.

  • This isoform adopts a closed, inactive and only dimeric conformation in which both, the interaction with the DNA as well as with the transcriptional machinery is significantly
    reduced[47] The inhibition is achieved by blocking the tetramerization interface of the oligomerization domain with a six-stranded anti-parallel beta-sheet.

  • Work by a collaboration between several CEF groups unravelled the molecular nature of Bowen-Conradi syndrome by demonstrating that the disease-causing point mutation of the
    ribosome biogenesis factor Nep1 impairs its nucleolar localisation and RNA binding.

  • In humans, there are six different proteins, which play a central role by connecting nascent autophagosome membranes and cargo-loaded autophagy receptors to facilitate engulfment,
    sometimes mediated or supported by additional adaptor proteins.

  • The view that proteins act as single entities has been replaced with the concept suggesting that dynamic reorganization of multimeric soluble complexes annotated as signalosomes
    is essential for signal transmission in the cell.

  • [50] Complexes involved in tumorigenesis were studied by several CEF groups, including the leukemogenic AF4-MLL fusion protein[51] and RIP1-containing cytosolic complexes
    that are critical for the initiation and fine-tuning of different forms of cell death, i.e.

  • [57] The mechanism of membrane insertion of tail-anchored proteins was studied by structural and biochemical characterization of the interaction of the soluble Get3 protein
    with the cytoplasmatic domains of the membrane-bound receptors Get1 and Get2.

  • Additional foci of CEF research were genetic quality control in oocytes and epithelial stem cells by the p53 protein and the regulation of and by kinases.

  • Regulation of the activity of these complexes is achieved by their dynamic composition as well as by post-translational modifications (PTMs) of proteins.

  • [75][76] Another study, in collaboration with Edinburg University, analysed the RNA helicase Prp43 by crosslinking of RNA and analysis of cDNA (and provided first insights
    into the functional roles of this enzyme in ribosome biogenesis[77] CEF scientists also identified plant-specific ribosome biogenesis factors in A. thaliana with essential function in rRNA processing[78] and showed that the 60S-associated
    ribosome biogenesis factor LSG1-2 is required for 40S maturation in A.

  • Research into autophagy[edit] During selective autophagy, cargo is specifically targeted for degradation, and distinct cargo receptors have been described that regulate selectivity.

  • [84] Local maturation of the miRNA was found to be associated with a local reduction in protein synthesis, showing that localized miRNA maturation can modulate target gene
    expression with local and temporal precision.

  • CEF scientists evaluated members of the SR protein family for their potential to act as adaptors for nuclear export factor 1 (NXF1) and thereby couple pre-mRNA processing
    to mRNA export.

  • Structural description of RNA elements and their dynamics[edit] The combination of high-resolution NMR-based analysis of RNA structures[59][60] and time-resolved ligand-induced
    refolding of RNAs by caging distinct conformations[61] together with pulsed electron paramagnetic resonance methods after base-specific spin-labeling[62][63][64] and ultrafast laser spectroscopy of RNA dynamics[65][66] has led to the description
    of the structural dynamics of several RNAs.

  • CEF scientists have developed bromodomain inhibitors that can be used to study the function of these acetyl-lysine modification binding domains.

  • [35] CEF scientists also revealed the molecular mechanism of a novel type of phosphoribosyl-linked serine ubiquitination by the effector SdeA of the pathogen Legionella, which
    is very different from the canonical lysine-based ubiquitination mechanism.

  • CEF scientists also showed that for the guanine-sensing xpt-pbuX riboswitch of B. subtilis, the conformation of the full-length transcripts is static: it exclusively populates
    the functional off-state but cannot switch to the on-state, regardless of the presence or absence of ligand.

  • [79] Distribution of RNA-modifying enzymes and RNA molecules[edit] The dynamics of RNPs in native environments in eukaryotic cells were visualized and quantified using high-resolution

  • They further discovered that reticulon-type proteins act as ER-specific autophagy receptors and simulated their effect on the membrane curvature.

  • [82] They found that >1000 endogenous mRNAs required individual SR proteins for nuclear export in vivo.

  • CEF Research Area B – Composition and dynamics of macromolecular complexes in quality control and signalling[edit] The characterization of function and structural composition
    of signalling complexes controlling cellular quality control programs was one of the major topics of CEF research.

  • [130] New building principles for DNA-nanoarchitectures have been established in CEF Also, new RNA riboswitches have been designed that can be triggered with small metabolites,
    exogenous molecules, or by temperature changes, as well as aptamers or self-cleaving ribozymes, which can be used to control gene expression in vivo.

  • [134] Making macromolecules further accessible on the nano-scale for manipulation, CEF developed generally applicable methods to organize macromolecular complexes in two dimensions
    with very high precision, as well as small synthetic gatekeepers and novel “light switches” to control biomolecular interactions and assembly of macromolecular complexes An approach to assemble three-dimensional protein networks by two-photon
    activation was developed.

  • CEF Research Area D – Design of macromolecular complexes[edit] A major focus of work in CEF was to develop and use methods and to explore proteins that enable modulating cellular
    and molecular function with light.

  • They also developed an approach for the chemo‐enzymatic synthesis of position‐specifically modified RNA for biophysical studies including light control.

  • [103] They also generated several mutant ChR2 versions with altered ion conductance (for example increased Ca2+-permeability in “CatCh”, a Ca2+ transporting channelrhodopsin)
    or kinetics, representing highly useful additions to the optogenetic toolbox .

  • [127] They also developed a minimal light‐switchable module enabling the formation of an intermolecular and conformationally well‐defined DNA G‐quadruplex structure with a
    photoswitchable azobenzene residue as part of the backbone structure.

  • A rational and minimally invasive protein engineering approach was used that left the molecular mechanisms of FASs unchanged and identified five mutations that can make baker’s
    yeast produce short-chain fatty acids.

  • [129] Using light-inducible antimiRs, CEF scientists also investigated if locally restricted target miRNA activity has a therapeutic benefit in diabetic wound healing and
    found that light can be used to locally activate therapeutically active antimiRs in vivo.

  • The study showed that DNP-enhanced solid-state NMR is a key method for bridging the gap between X-ray–based structure analysis and functional studies towards a highly resolved
    molecular picture .

  • Optochemical approaches, in contrast, use chemically engineered molecules to achieve light-effects in biological tissue.

  • [123][124] Wavelength-selective light-triggering was established for nucleic acids[125] as well as three-dimensional control of DNA hybridization by orthogonal two-colour
    two-photon uncaging.

  • CEF scientists together with colleagues from other German universities developed a novel approach to alter the functional properties of rhodopsin optogenetic tools, namely
    by modifications of the retinal chromophore.

  • [122] Furthermore, light-activatable interaction of DNA nanoarchitectures, light-dependent conformational changes in nucleic acids, light-dependent RNA interference and light-dependent
    transcription were realized.

  • [113] CEF scientists have also used optogenetic tools for the analysis of neural circuits and how they drive behaviour.

  • [161][162] Other novel light microscopy techniques used by CEF scientists include techniques that provide single-molecule sensitivity and a spatial resolution below the diffraction
    limit to study the structural organization of biomolecules in cells.

  • Software tools developed by CEF scientists include for example SuReSim, a software developed in collaboration with Heidelberg University, that simulates localization data
    of arbitrary three-dimensional structures represented by ground truth models, allowing users to systematically explore how changing experimental parameters can affect potential imaging outcomes.

  • This work was the first NMR study of a eukaryotic transporter protein complex and demonstrated the power of solid-state NMR in this field[170] They also demonstrated the power
    of DNP-enhanced solid-state NMR to bridge the gap between functional and structural data and models.

  • CEF Research Area E – Methods for studying macromolecular complexes[edit] The development of cutting-edge methodologies, including electron paramagnetic resonance, time-resolved
    nuclear magnetic resonance spectroscopy, advanced fluorescence microscopy, as well as optogenetics and optochemical biology has been instrumental in the research efforts of CEF.

  • Studies included molecular systems like optical switches, natural and non-natural photosynthetic model systems and membrane protein complexes.

  • The study also demonstrated for the first-time the feasibility to resolve equilibrium populations at multiple domains and their interdependence for global conformational changes
    in a large membrane protein complex.

  • Spectroscopy methods[edit] A wide range of spectroscopy methods for biological applications were available within CEF and CEF scientists have made significant progress in
    further developing biomolecular NMR and EPR.

  • [166][167] Collectively, the new tools provide additional avenues to specifically manipulate and trap cellular proteins, and, at the same time, for high-resolution read-out
    by single-molecule based microscopy.

  • [165] The close collaborative teamwork of the consortium allowed tackling two major challenges in live-cell as well as single-molecule localization microscopy: efficient delivery
    of fluorophores across cell membranes and high-density protein tracing by ultra small labels.

  • By investing in this new technology, CEF members have been able to speed up structure determination and also solve the structures of macromolecular complexes that were not
    amenable to x-ray crystallography studies.

  • [157] CEF scientists used LSFM, for example, to image in detail the complete embryonic development of different evolutionary unrelated insects and to establish the rules and
    self-organizing properties of post-embryonic plant organ cell division patterns.

  • This is an essential prerequisite to allow conclusions about the solution state protein complex, based on the gas phase measurements.

  • This method enables the observation of extremely fast chemical and biological reactions in real time involving a wide variety of molecules from small organic compounds to
    complex enzymes.

  • [172] PELDOR spectroscopy proved to be a versatile tool for structural investigations of proteins, even in the cellular environment.

  • Information-mining algorithms exploit structural data from various techniques, identify distinct macromolecules and computationally fit atomic resolution structures in the
    cellular tomograms, thereby bridging the resolution gap.

  • CEF contributed to the development of laser-induced liquid bead ion desorption mass spectrometry (LILBID), a method developed at Goethe University that is especially suited
    to the analysis of large membrane protein complexes.

  • CEF scientists used custom-tailored code and pipelines for fast and efficient analysis[191] of omics data, with a primary focus on protein-RNA interactions and posttranscriptional

  • Examples of these studies include the investigation and deciphering of the dynamics of photoswitchable or photolabile compounds as basis for the design of photoresponsive
    biomacromolecules, of the primary reaction dynamics of channelrhodopsin-2 (ChR2) and of the conformational dynamics of antibiotic-binding aptamers: Photochromic spiropyrans are organic molecules that can be used for the triggering of biological

  • [174] A challenge in native mass spectrometry is maintaining the features of the proteins of interest, such as oligomeric state, bound ligands, or the conformation of the
    protein complex, during the transfer from the solution to the gas phase.

  • Because with LSFM biological specimens survive long-term three-dimensional imaging at high spatiotemporal resolution, such microscopes have become the tool of choice in developmental

  • Advantages of mass spectrometry compared to other methods like X-ray crystallography or nuclear magnetic resonance are for instance its lower limits of detection, its speed
    and its capability to deal with heterogeneous samples.

  • Direct electron detectors, in the development of which the MPI of Biophysics was involved, have exceeded all expectations[152][153] With these detectors, images can be captured
    with much higher contrast than with the CCD cameras previously used and have led to amazing progress in structural biology.

  • [158][159][160] The large amount of data produced by advanced light microscopy has made automated image analysis a necessity and CEF has contributed to improved data processing
    and modelling of advanced light microscopy data.

  • [163] Using the newly developed techniques, CEF scientists were able to establish the role of the linear ubiquitin coat around the cytosolic pathogen Salmonella Typhimurium
    as the local NF-κB signalling platform and provided insights into the function of OTULIN in NF-κB activation during bacterial pathogenesis.

  • Bridging between fundamental physics, chemistry and biology, CEF scientists studied biomolecular processes over a broad resolution range, from quantum mechanics to chemical
    kinetics, from atomistic descriptions of physical processes and chemical reactions in molecular dynamics (MD) simulations to highly coarse-grained models of the non-equilibrium operation of molecular machines and network descriptions of protein

  • Such tomograms contain a large amount of information as they are essentially a three-dimensional map of the cellular proteome and depict the whole network of macromolecular

  • Theoretical biophysics and bioinformatics[edit] Method development in theoretical biophysics plays an increasingly important role in the study of macromolecular complexes
    and has made essential contributions to many studies in the other research areas of CEF.

  • They also develops algorithms to solve problems in molecular biology, ranging from atomic protein structure analysis to computational systems biology.

  • Their goal is to develop detailed and quantitative descriptions of key biomolecular processes, including energy conversion, molecular transport, signal transduction, and enzymatic


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