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Unravelling the complexity of membranes

In 2020, an HFSP Research Grant – Program was awarded to Electra Gizeli, Toshio Ando, Andrew J. Spakowitz and Marino Zerial to investigate the self-organisation and mechanical properties of biological membranes. Principal Investigator Electra Gizeli discusses the goals of the project and the planned approaches by the different members of the multidisciplinary team.

Gaining insights into the structure and function of biological membranes is a prerequisite for understanding cell organisation. However, progress made on the discovery of molecular components (lipids and proteins) alone is insufficient to understand the structure or function of these membranes. Knowledge of emerging properties arising from the collective behaviour of proteins self-organised into supra-molecular structures is becoming central to understanding cell organisation and function. Progress in this area requires theoretical and experimental approaches merged into an interdisciplinary and innovative research program as proposed here.  

Principal Investigator Electra Gizeli, photo credit: Lila Kalogeraki

We propose to elucidate the self-organisation and mechanical properties of biological membranes by following a multidisciplinary approach using soft-matter physics, biosensing, microscopy, biochemistry and cell biology. We focus on the early endosome membrane harbouring the vesicle tethering/fusion machinery. The 200nm long coiled coil protein EEA1 tethers vesicles bearing the small GTPase Rab5. Binding of Rab5 to EEA1 induces an allosteric transition from extended to flexible, thereby mechanically pulling the membranes closer for fusion. In addition, the high local density of EEA1 allows it to form a novel switchable polymer brush on the endosomal membrane. We propose to investigate this membrane system from the single-molecule level to the collective properties of the polymer brush by: 

1) studying how chemical energy is harnessed to control the active and switchable EEA1 forming a polymer brush using soft-condensed matter and polymer physics, and multi-scale models; 
2) investigating the cycle of EEA1 collapse and extension on a supported lipid bilayer (SLB) of different lipid composition with an acoustic wave device; and 
3) monitoring structural changes and mechanical properties of EEA1 by high-speed atomic force microscopy (AFM).

Our project has the merit to generate knowledge on the biochemical/biophysical mechanism of a membrane tether system and its collective and non-equilibrium properties, both relevant to all sub-cellular membrane organelles. The combined use of polymer simulations, acoustic waves for real-time monitoring of EEA1 conformational change, AFM to probe the elastic properties of single EEA1 molecules and cellular studies will provide insights not only into the mechanism of recognition and tethering of vesicles, but also into the physical properties of cellular membranes.

HFSP award information

Research Grant - Program (RGP0019/2020): Self-organization and biomechanical properties of the endosomal membrane

Principal investigator: Electra Gizeli, Biosensors Lab, Institute of Molecular Biology & Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Greece
Co-investigator: Toshio Ando, WPI Nano Life Science Institute, Kanazawa University, Japan 
Co-investigator: Andrew J. Spakowitz, Dept. of Chemical Engineering, Stanford University, USA
Co-investigator: Marino Zerial, Principles of cell and tissue organization, MPI of Molecular Cell Biology and Genetics, Dresden, Germany (nationality: Italy)

 

 

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