CNRS - AIX MARSEILLE UNIV: UMR7257


Our laboratory


The Architecture et Fonction des Macromolécules Biologiques (AFMB) laboratory, overseen by the CNRS and AMU, is a center of structural biology localized on the Luminy campus in the South of Marseilles, France, and in partnership with INRA under contract. The aim of our researches is to depict the architecture of proteins or macromolecular assemblies at the molecular level to understand the biological mechanisms which they govern. The description of interactions between macromolecules or a macromolecule and a ligand is also crucial to manipulate these complex molecules. Finally, to understand the molecular diversity of members of some protein families, we also analyze the big data issued from large-scale genome sequencing centers.


Seminars
  • Monday 25th of January at 2pm: Nabil G. Seidah, Lab of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM), Canada, "Diverse physiological roles of the proprotein convertases & their implications in pathologies: COVID-19 and the processing of the SARS-CoV-2 Spike protein"
    The AFMB seminars are currently webinars. If you are interested in joining one or more webinars please send an email to seminar@afmb.univ-mrs.fr to request the connection link.

    Abstract (...)

    Abstract
    The proprotein convertases (PCs, genes PCSKs) constitute a family of 9 mammalian secretory serine proteases that play diverse critical roles in health and disease. An overview of the different physiological and pathological functions of the PCs will be presented, emphasizing the implication of the 3rd PC-family member Furin in viral infections, such SARS-CoV-2 responsible for the pandemic spread of COVID-19. The Spike (S)-protein of SARS-CoV-2 binds host-cell receptor ACE2 and requires proteolytic “priming” (S1/S2) and “fusion-activation” (S2’) for viral entry. The S-protein furin-like motifs PRRAR685↓ and KPSKR815↓ indicated that proprotein convertases promote virus entry. We demonstrate that Furin and the 5th PC-family member PC5A induce cleavage at both sites, ACE2 enhances S2’ processing, and their pharmacological inhibition (BOS-inhibitors) block endogenous cleavages. S1/S2-mutations (S1/S2) limit S-protein-mediated cell-to-cell fusion, similarly to BOS-inhibitors. Unexpectedly, TMPRSS2 does not cleave at S1/S2 or S2’, but it can: (i) cleave/inactivate S-protein into S2a/S2b; (ii) shed ACE2; (iii) cleave S1-subunit into secreted S1’, activities inhibited by Camostat. In lung-derived Calu-3 cells, BOS-inhibitors and µS1/S2 severely curtail “pH-independent” viral entry, and BOS-inhibitors alone/with Camostat potently reduce infectious viral titer and cytopathic effects. Overall, our results show that: furin plays a critical role in generating fusion-competent S-protein, and indirectly, TMPRSS2 promotes viral entry, supporting furin and TMPRSS2 inhibitors as potential antivirals against SARS-CoV-2.
    All seminars
News
  • Isabelle Imbert nominated to the rank of “Knight in the National Order of the Legion of Honour”!
  • The work of Rhian Jones, Juan Reguera and colleagues on viral replication highlighted by the INSB
  • The work of Sonia Longhi and collaborators on "intrinsically disordered" proteins highlighted by the INSB
  • "The origin of SARS-CoV-2 is being seriously questioned"
    Etienne Decroly discusses the various hypotheses for le journal du CNRS
  • The Bruno Canard’s team spotlighted for its work on COVID on CNRS/Le journal
  • The work of Ashleigh Shannon and Bruno Canard’s team spotlighted by the INSB dept of CNRS



AFMB - UMR7257 CNRS - Aix-Marseille Univ. - Case 932
163 Avenue de Luminy 13288 Marseille CEDEX 09 FRANCE


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