Bio

Professional Education


  • Bachelor of Science, Eidgenossische Technische Hochschule (ETH Zurich) (2010)
  • Master of Science, Eidgenossische Technische Hochschule (ETH Zurich) (2012)
  • Doctor of Science, Eidgenossische Technische Hochschule (ETH Zurich) (2017)

Research & Scholarship

Lab Affiliations


Publications

All Publications


  • A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling. Nature communications Beautrait, A., Paradis, J. S., Zimmerman, B., Giubilaro, J., Nikolajev, L., Armando, S., Kobayashi, H., Yamani, L., Namkung, Y., Heydenreich, F. M., Khoury, E., Audet, M., Roux, P. P., Veprintsev, D. B., Laporte, S. A., Bouvier, M. 2017; 8: 15054

    Abstract

    In addition to G protein-coupled receptor (GPCR) desensitization and endocytosis, β-arrestin recruitment to ligand-stimulated GPCRs promotes non-canonical signalling cascades. Distinguishing the respective contributions of β-arrestin recruitment to the receptor and β-arrestin-promoted endocytosis in propagating receptor signalling has been limited by the lack of selective analytical tools. Here, using a combination of virtual screening and cell-based assays, we have identified a small molecule that selectively inhibits the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP2 without interfering with the formation of receptor/β-arrestin complexes. This selective β-arrestin/β2-adaptin inhibitor (Barbadin) blocks agonist-promoted endocytosis of the prototypical β2-adrenergic (β2AR), V2-vasopressin (V2R) and angiotensin-II type-1 (AT1R) receptors, but does not affect β-arrestin-independent (transferrin) or AP2-independent (endothelin-A) receptor internalization. Interestingly, Barbadin fully blocks V2R-stimulated ERK1/2 activation and blunts cAMP accumulation promoted by both V2R and β2AR, supporting the concept of β-arrestin/AP2-dependent signalling for both G protein-dependent and -independent pathways.

    View details for PubMedID 28416805

    View details for PubMedCentralID PMC5399295

  • Diverse activation pathways in class A GPCRs converge near the G-protein-coupling region. Nature Venkatakrishnan, A. J., Deupi, X., Lebon, G., Heydenreich, F. M., Flock, T., Miljus, T., Balaji, S., Bouvier, M., Veprintsev, D. B., Tate, C. G., Schertler, G. F., Babu, M. M. 2016; 536 (7617): 484-487

    Abstract

    Class A G-protein-coupled receptors (GPCRs) are a large family of membrane proteins that mediate a wide variety of physiological functions, including vision, neurotransmission and immune responses. They are the targets of nearly one-third of all prescribed medicinal drugs such as beta blockers and antipsychotics. GPCR activation is facilitated by extracellular ligands and leads to the recruitment of intracellular G proteins. Structural rearrangements of residue contacts in the transmembrane domain serve as 'activation pathways' that connect the ligand-binding pocket to the G-protein-coupling region within the receptor. In order to investigate the similarities in activation pathways across class A GPCRs, we analysed 27 GPCRs from diverse subgroups for which structures of active, inactive or both states were available. Here we show that, despite the diversity in activation pathways between receptors, the pathways converge near the G-protein-coupling region. This convergence is mediated by a highly conserved structural rearrangement of residue contacts between transmembrane helices 3, 6 and 7 that releases G-protein-contacting residues. The convergence of activation pathways may explain how the activation steps initiated by diverse ligands enable GPCRs to bind a common repertoire of G proteins.

    View details for PubMedID 27525504

    View details for PubMedCentralID PMC5008462

  • Stabilization of G protein-coupled receptors by point mutations FRONTIERS IN PHARMACOLOGY Heydenreich, F. M., Vuckovic, Z., Matkovic, M., Veprintsev, D. B. 2015; 6: 82

    Abstract

    G protein-coupled receptors (GPCRs) are flexible integral membrane proteins involved in transmembrane signaling. Their involvement in many physiological processes makes them interesting targets for drug development. Determination of the structure of these receptors will help to design more specific drugs, however, their structural characterization has so far been hampered by the low expression and their inherent instability in detergents which made protein engineering indispensable for structural and biophysical characterization. Several approaches to stabilize the receptors in a particular conformation have led to breakthroughs in GPCR structure determination. These include truncations of the flexible regions, stabilization by antibodies and nanobodies, fusion partners, high affinity and covalently bound ligands as well as conformational stabilization by mutagenesis. In this review we focus on stabilization of GPCRs by insertion of point mutations, which lead to increased conformational and thermal stability as well as improved expression levels. We summarize existing mutagenesis strategies with different coverage of GPCR sequence space and depth of information, design and transferability of mutations and the molecular basis for stabilization. We also discuss whether mutations alter the structure and pharmacological properties of GPCRs.

    View details for PubMedID 25941489

  • AAscan, PCRdesign and MutantChecker: A Suite of Programs for Primer Design and Sequence Analysis for High-Throughput Scanning Mutagenesis PLOS ONE Sun, D., Ostermaier, M. K., Heydenreich, F. M., Mayer, D., Jaussi, R., Standfuss, J., Veprintsev, D. B. 2013; 8 (10): e78878

    Abstract

    Scanning mutagenesis is a powerful protein engineering technique used to study protein structure-function relationship, map binding sites and design more stable proteins or proteins with altered properties. One of the time-consuming tasks encountered in application of this technique is the design of primers for site-directed mutagenesis. Here we present an open-source multi-platform software AAscan developed to design primers for this task according to a set of empirical rules such as melting temperature, overall length, length of overlap regions, and presence of GC clamps at the 3' end, for any desired substitution. We also describe additional software tools which are used to analyse a large number of sequencing results for the presence of desired mutations, as well as related software to design primers for ligation independent cloning. We have used AAscan software to design primers to make over 700 mutants, with a success rate of over 80%. We hope that the open-source nature of our software and ready availability of freeware tools used for its development will facilitate its adaptation and further development. The software is distributed under GPLv3 licence and is available at http://www.psi.ch/lbr/aascan.

    View details for PubMedID 24205336