Spectacular images of a molecule that carries omega-3 fatty acids into the brain could open a door for neurological therapeutics to be delivered to the brain.
We have succeeded in obtaining a three-dimensional structure of the transporter protein, which provides a gateway for omega-3 fatty acids into the brain. In this structure we can see how omega-3 fatty acids bind to the transporter. This information could enable the development of drugs that mimic omega-3 fatty acids to hijack this system and get into the brain. “
Rosemary J. Cater, PhD, first author, Simons Society Fellow at the Mancia Lab at Columbia University’s Vagelos College of Physicians and Surgeons
The study was published online in the journal Nature on June 16.
A major challenge in treating neurological disorders is getting drugs across the blood-brain barrier – a layer of tightly packed cells that lines the blood vessels of the brain, eager to prevent toxins, pathogens, and some nutrients from entering the brain. Unfortunately, the layer also blocks many drugs that are otherwise promising candidates for treating neurological diseases.
Essential nutrients such as omega-3 fatty acids require the support of special transport proteins, which they specifically recognize and overcome this barrier. “The vans are like bouncers in a club who only let in molecules with invitations or backstage passages,” says Cater.
The van – or bouncer – that lets in omega-3 fatty acids is called MFSD2A and is the focus of Caters research. “If we understand what MFSD2A looks like and how omega-3s are drawn across the blood-brain barrier, we can get the information we need to develop drugs that can trick that bouncer and get tickets.”
To visualize MFSD2A, Cater used a technique called single particle cryo-electron microscopy.
“The beauty of this technique is that we can see the shape of the transporter with details down to a fraction of a billionth of a meter,” says Filippo Mancia, PhD, co-lead of the study, associate professor of physiology and cellular biophysics at Vagelos College of Physicians and Surgeons from Columbia University and an expert on the structure and function of membrane proteins. “This information is crucial to understand how the transporter works at the molecular level.”
For cryo-EM analysis, protein molecules are suspended in a thin layer of ice under an electron microscope. Powerful cameras take millions of images of the proteins from countless angles, which can then be put together to form a 3D map.
Researchers can use this map to build a 3D model of the protein and put each atom in its place. “It reminds me of solving a puzzle,” explains Mancia. This technique has become remarkably powerful in visualizing biological molecules in recent years, thanks in part to Joachim Frank, PhD, Professor of Biochemistry and Molecular Biophysics at Columbia University’s Vagelos College of Physicians and Surgeons, who won the 2017 Nobel Prize for his role in development of data analysis algorithms for cryo-electron microscopy.
“Our structure shows that MFSD2A has a bowl-like shape and that omega-3 fatty acids bind to a specific side of that bowl,” explains Cater. “The shell is upside down and facing the inside of the cell, but this is just a single 3D snapshot of the protein that has to move in real life to carry the omega-3 fatty acids. To understand exactly how it works, we need both. “Several different snapshots or, even better, a film of the transporter in motion.”
To understand what these movements might look like, a second co-lead on the study, George Khelashvili, PhD, assistant professor of physiology and biophysics at Weill Cornell Medicine, used the 3-D model of the protein as a starting point to run computer simulations that revealed how the van moves and adjusts its shape to release omega-3 fatty acids into the brain. A third co-leader of the study, David Silver, PhD, professor at Duke-NUS Medical School in Singapore and a pioneer of MFSD2A biology, together with his team tested and confirmed hypotheses derived from the structure and computer simulations of how MFSD2A works were derived to locate certain parts of the protein that are important.
The team also included researchers from the New York Structural Biology Center, the University of Chicago, and the University of Arizona, all of whom used their specific skills to make this project possible.
The team is now investigating how the transporter recognizes omega-3 fatty acids from the bloodstream for the first time. “But our study has already given us tremendous insight into the supply of omega-3 fatty acids to the brain by MFSD2A and we are really excited to see where our results lead,” says Cater.
Irving Medical Center at Columbia University
Cater, RJ et al. (2021) Structural basis of the omega-3 fatty acid transport across the blood-brain barrier. Nature. doi.org/10.1038/s41586-021-03650-9.