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Scientific result | Molecular mechanisms | Cell and molecular imaging
By studying the self-assembly of a hormone-derived peptide in the presence of lipid membranes, a team of the SB2SM (Joliot Institute / I2BC) in collaboration with the University of Rennes 1 and Ipsen biopharmaceutical group, shows how the interactions electrostatic type modify the structures of the assemblies formed by each of these molecules alone in solution.
One of the pathological processes well described in Alzheimer's, Parkinson's or Huntington's diseases is the accumulation in the brain of proteins which, by acquiring an abnormal conformation, aggregate and form "plates" or fibers. In the case of Alzheimer's disease, the beta-amyloid peptide, produced by successive cleavages of the APP membrane protein, rapidly adopts after its production a conformation that gives it the ability to self-assemble, first in oligomers then in fibers and plates. But environmental factors, such as the proximity of cell membranes, influence this self-assembly. For instance, it is known that ganglioside GM1 (a glycosphingolipid) increases the oligomerization rate of the beta-amyloid peptide.
How to explain this influence? What are the membrane / peptide interactions that promote or destabilize such an organization? An I2BC team is studying the mechanisms of peptide self-assembly and the physicochemical factors that govern them. In collaboration with the University of Rennes 1, Ipsen and the Synchrotron Soleil, they studied the influence of lipid membranes on the self-assembly of lanreotide. This therapeutic analogue of somatostatin hormone is a positively charged oligopeptide of eight amino acids. In water, lanreotide forms hollow nanotubes of perfectly monodisperse diameter whose crystalline wall is formed by a bilayer of peptides. The surfaces of the bilayer are hydrophilic and its core hydrophobic. This peptide is a unique model for studying and understanding the influence of surrounding physicochemical parameters on the self-assembly process: the structure of lanreotide nanotubes is perfectly known and characterized making easy the identification and understanding of any even small changes of the self-assemble architecture.
In an article published in Langmuir, the researchers show that the interaction between the dicationic peptide and negatively charged membranes (in the form of liposomes) induces the formation of self-assembled structures, whose morphology depends on the ratio between the positive charges of lanreotide and negative ones lipids of the membrane. According to this ratio between charges, the interaction between lanreotide and liposomes successively causes the bursting of liposomes, the stacking of lamellae alternately formed of lipid bilayers and peptide bilayers and the winding of these multilayered structures to form, in conditions close to electroneutrality a nanometric structure similar to rolls of parchment, "nanoscrolls". The resolution of the molecular structure of these complex assemblies shows how the strong electrostatic interaction between these two types of molecules modifies the structures they form independently in solution.
These nanoscrolls are reminiscent of the myelin sheath, a lamellar structure that surrounds the axons of certain neurons and results from the superposition of several rounds of plasma membrane of a Schwann cell. Membrane proteins and intracytoplasmic proteins that are directly involved in the tight compaction of the Schwann cell membrane are positively charged. The forces that govern this compaction are essentially electrostatic. The study shows that lanreotide is a simple model for studying not only the structure of peptide self-assemblies but also the mechanisms of their formation and the parameters that can destabilize these supramolecular buildings.
Chervy P, Petcut
C, Rault D, Meriadec C, Bizien T, François
K, Richard J, Chassaing C, Benamar N, Artzner F, Paternostre M. Organic Nanoscrolls from electrostatic interactions
between peptides and lipids: assembly steps and structure. | Langmuir, 2019
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.