Project description DEENESFRITPL Mechanistic insight into the regulation of MICAL signalling MICAL enzymes are fundamental for many cytoskeleton-driven processes including axon guidance, cell morphology, synaptogenesis and neuronal plasticity. They directly bind to actin filaments and participate in their dynamic disassembly. The scope of the EU-funded MICAL project is to understand the molecular mechanisms underlying MICAL signalling with particular emphasis on their activation and autoinhibition. Using state-of-the-art methodologies, scientists will elucidate the high-resolution structure of MICAL as well as other proteins, revealing important information on their molecular interactions. The project's results will unveil new possibilities in the manipulation of MICAL-driven signalling and help develop novel treatments for neurological disorders. Show the project objective Hide the project objective Objective MICALs are a family of redox enzymes that directly bind and disassemble actin filaments. An increasing body of evidence in recent years indicates that MICALs play essential roles in many tissues for myriad activities requiring discrete changes in the cytoskeleton, including axon guidance, cell morphology, synaptogenesis and neuronal plasticity. MICALs are a component of classical signalling pathways and are best known as effectors for semaphorin-plexin signalling. Although the field has made enormous advances in understanding MICAL function at the level of genetic and cellular experiments, our knowledge of the molecular-level mechanisms of MICAL signalling in cytoskeletal dynamics remains poorly understood.The overarching aim of this proposal is to understand the molecular mechanisms underlying MICAL signalling. I aim to address two fundamental and long-standing questions: (1) How do MICAL proteins precisely turn their activity on and off? (2) How do cytoplasmic segments of plexins pass the signal on to MICALs and what mechanisms control signalling? I will use a hybrid approach integrating single particle cryoEM with high-resolution X-ray crystallography to determine the overall architecture of MICAL and to elucidate molecular mechanisms of MICAL autoinhibition. In parallel, I will aim to determine the high-resolution structure of MICAL in complex with plexin to dissect molecular mechanisms of MICAL activation.All previous attempts to tease out the mechanisms governing MICAL signalling failed because full-length MICAL is expressed at a relatively low level in many expression systems. The project will greatly benefit from my previously developed protocol describing the production of MICALs in milligram quantities. Our findings will reveal fundamental principles of MICAL signalling, which will open new possibilities in the manipulation of cell signalling, and pave the way towards the treatment of MICAL associated neurological disorders. Fields of science natural sciencesbiological sciencesneurobiologynatural sciencesbiological sciencescell biologycell signalingnatural sciencesearth and related environmental sciencesgeologymineralogycrystallographymedical and health sciencesbasic medicineneurologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes Keywords MICAL signalling plexin cytoskeletal dynamics semaphorin autoinhibition Programme(s) H2020-EU.4. - SPREADING EXCELLENCE AND WIDENING PARTICIPATION Main Programme Topic(s) WF-02-2019 - Widening Fellowships Call for proposal H2020-WF-2018-2020 See other projects for this call Sub call H2020-WF-02-2019 Funding Scheme MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF) Coordinator UNIVERZITA KARLOVA Net EU contribution € 156 980,64 Address Ovocny trh 560/5 116 36 Praha 1 Czechia See on map Region Česko Praha Hlavní město Praha Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
