Poster Presentation 2014 International Biophysics Congress

Protein-induced millisecond structural transitions in lipid membrane nanoparticles (#300)

Angelina Angelova 1 , Borislav Angelov 2 , Markus Drechsler 3 , Sylviane Lesieur 1
  1. CNRS UMR8612, Institut Galien Paris-Sud, Université Paris-Sud 11, Chatenay-Malabry, France
  2. Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic
  3. Laboratory for Soft Matter Electron Microscopy, Bayreuth Institute of Macromolecular Research, University of Bayreuth, Bayreuth, Germany

The purpose of this work is to investigate the mechanism and the kinetic pathway of lipid membrane/neurotrophic protein assembly and ordering at the nanoscale. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is the most abundant neurotrophin in the mammalian central nervous system. It exerts trophic effects on a wide range of neuronal and non-neuronal cells. BDNF-induced signaling is crucial for neuronal survival, function, morphogenesis, and plasticity. The activation of the signal transduction pathway requires neurotrophin delivery at target sites and BDNF binding to its membrane receptor TrkB (tropomyosin-related kinase, type B). Nanostructured lipid-membrane-based carriers may generate multicompartment reservoirs for sustained neurotrophin release. Thus, they may stimulate "big signals" in the regulation of the cell signaling. Here, unprecedented formation of multi-phase nanoparticles, taking place upon dynamic assembly of BDNF at flexible membrane interfaces, is established by means of time-resolved small-angle X-ray scattering (SAXS) and cryo-TEM imaging of nanoparticulate systems. Evidence is presented that bound BDNF may increase the curvature of flat membrane structures and reduce the curvature of tubular (HII-phase) lipid structures. As a result, the fluid lipid membranes change their shape and structural organization in response to the neurotrophin binding and trafficking along the lipid/water interfaces. The membrane interfaces adopt states of continuously changing curvatures, which most properly fit to the protein conformation and charge under the dynamic conditions of protein crowding. The bicontinuous cubic channel network architecture in the lipid nanoparticles is found to be the most favourable membrane state for the BDNF trafficking.

  1. Angelov, B.; Angelova, A.; Filippov, S.; Drechsler, M.; Stepanek, P.; Lesieur, S. Multicompartment lipid cubic nanoparticles with high protein upload: Millisecond dynamics of formation. ACS Nano, 2014, DOI 10.1021/nn5012946.
  2. Angelov, B.; Angelova, A.; Papahadjopoulos-Sternberg, B.; Hoffmann, S.V.; Nicolas, V.; Lesieur, S. Protein-containing PEGylated cubosomic particles: Freeze-fracture electron microscopy and synchrotron radiation circular dichroism study, J. Phys. Chem. B, 2012, 116, 7676-7686.
  3. Angelova, A.; Angelov, B.; Mutafchieva, R.; Lesieur, S.; Couvreur, P. Self-assembled multicompartment liquid crystalline lipid carriers for protein, peptide, and nucleic acid drug delivery. Accounts of Chemical Research 2011, 44, 147-156.
  4. Angelova, A.; Angelov, B.; Garamus, V.M.; Couvreur, P.; Lesieur, S. Small-angle X-ray scattering investigations of biomolecular confinement, loading, and release from liquid crystalline nanochannel assemblies, J. Phys. Chem. Lett., 2012, 3, 445-457.
  5. Angelov, B.; Angelova, A.; Garamus, V.M.; Drechsler, M.; Willumeit, R.; Mutafchieva, R.; Stepanek, P.; Lesieur, S. Earliest stage of the tetrahedral nanochannel formation in cubosome particles from unilamellar nanovesicles, Langmuir, 2012, 28, 16647–16655.
  6. Angelova, A.; Angelov, B.; Drechsler, M.; Lesieur, S. Neurotrophin delivery using nanotechnology. Drug Discovery Today, 2013, 18, 1263–1271.