CNRS Chemistry welcomes Ayyalusamy Ramamoorthy as the CNRS Ambassador in Chemical Sciences

A great deal of research is being carried out to understand the different functions of membrane proteins with a view to using them for biomedical or biotechnological purposes. Can you tell us more about your team's work in this field?

Despite recent advances in crystallography and cryo-EM, membrane proteins remain a challenge for atomic-scale structural studies. These proteins, associated with the plasma membrane of cells, play crucial roles in many biological processes, including communication between the cell and its environment, transport of molecules, and maintenance of cell structure. Our research focuses on the development of NMR techniques to characterize the dynamic nature of these proteins at atomistic resolution, i.e. how they move within the membrane to carry out their function.  But also to learn more about their amphipathic* character, which enables them to perform specific functions such as forming channels for the passage of hydrophilic molecules.

As a first step, we sought to broaden the field of applications of bicelles. These structures, formed by an appropriate combination of lipids and detergents, are used as laboratory models for studying the biophysics of membranes and associated proteins.  We have succeeded in optimizing them to enable a combination of solution and solid-state NMR measurements essential for studying the dynamic structures of membrane proteins. More recently, we have made significant contributions to the development of nanodiscs for structural and functional studies of membrane-associated protein-protein complexes, which play a central role in cell function by orchestrating responses to signals and ensuring structural and functional cohesion. We have synthesized amphipathic polymers to isolate membrane proteins and associated lipids directly from cell membranes in nanodisc form. Nanodiscs are directly ready for structural and functional NMR studies and also by other biophysical/biochemical approaches, without the need for the detergents that are usually used to solubilize and stabilize them.

Our research on amyloid proteins** and intrinsically disordered proteins has revealed the mechanisms of their self-assembly leading to aggregation, the structures of early reaction intermediates (such as oligomers) and their catalytic role in nerve cell degeneration. This work has also enabled us to better understand the toxicity and prion-like propagation associated with amyloid diseases such as Alzheimer's and type 2 diabetes.

What progress can we expect in this area over the next few years?

We are now seeking to extend the applications of these membrane protein nanodiscs to the study of dynamic structures of protein-protein complexes associated with human diseases and also to accomplish the ultimate goal to understand the role of lipid membranes on the formation of toxic amyloid intermediates. We believe that these structural studies will be crucial for the development of compounds to treat amyloid diseases, and for our understanding of drug metabolism by enzymes such as cytochrome P450. In parallel, we will explore the interactions between biomolecules involved in different diseases. For example, studying the interactions between proteins associated with type 2 diabetes and Alzheimer's disease could reveal the molecular mechanisms underlying the relationship between these diseases. We also intend to study the effects of infectious diseases on neurological disorders.

Our efforts will continue to focus on multidisciplinary techniques using magnetic resonance (including NMR, EPR and MRI) and biochemical/biological approaches to provide answers to these challenging and medically essential questions.

As Ambassador for Chemical Sciences in France, do you have any particular expectations of this upcoming tour? 

I have always enjoyed my stays in France and my interactions with colleagues from various institutions and disciplines. As our research is multidisciplinary, I will be delighted to take advantage of this trip to broaden and diversify existing scientific interactions and partnerships. I also plan to gain valuable insights from the recent discoveries of the research groups I will be visiting. I also hope to engage in discussions with junior researchers, recruit students and post-doctoral fellows, and welcome visiting scientists to participate in the research conducted in my laboratory. 

* In 2019, CNRS Institute of Chemistry has initiated a program called “Ambassadors of Chemical Sciences in France”. Its ambition is to give prestigious foreign researchers an opportunity to visit a series of French laboratories active in their field. These visits not only include top-notch conferences by the ambassador, but are also a good opportunity to establish preliminary contacts and foster international collaborations for the visited French laboratories.

** The term amphipathic is used when a molecule has both hydrophobic and hydrophilic regions.

*** An amyloid protein is a protein that aggregates to form deposits called amyloid plaques in tissues or organs. These aggregates are often associated with neurodegenerative diseases such as Alzheimer's, Parkinson's...

Editor : CCdM