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Researchers from the Göttingen Cluster of Excellence Multiscale Bioimaging (MBExC) have uncovered the 3D structure of the membrane proteins myoferlin and dysferlin using high-resolution cryo-electron microscopy. The findings enable new approaches for the development of targeted drugs for the treatment of diseases such as muscle atrophy, hearing disorders and certain cancers. The results have been published in the scientific journal “The EMBO Journal”.
The cell membrane is a flexible protective layer that surrounds our cells, separates them from the environment and regulates the exchange of substances with the environment. How it protects itself from damage and which repair mechanisms are involved in its renewal is not yet understood in detail.
Researchers from the Institute of Auditory Neuroscience at the University Medical Center Göttingen (UMG) and the Cluster of Excellence “Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells” (MBExC), in collaboration with the Max Planck Institute for Multidisciplinary Sciences, have achieved a significant breakthrough in structural biology: For the first time, they were able to elucidate the high-resolution three-dimensional (3D) structure of the membrane proteins, myoferlin and dysferlin. These proteins belong to the “ferlin” family and play a central role in the repair of cell membranes - a process that is crucial for muscle function, heart health and even the development of cancer.
One ring to bind them all
Using state-of-the-art cryo-electron microscopy, the research team was able to decipher the structure. To do this, the membrane proteins were shock-frozen in a solution and then examined under an electron microscope at minus 193 degrees Celsius. The researchers took thousands of individual images of the molecules under the microscope and then used high-performance computers to calculate a 3D structure at almost atomic resolution. Using the images, they were able to show how ferlins adopt a compact ring structure in the presence of calcium and lipid membranes. This structural change is not a mere detail - it is the key to how ferlins influence membrane remodeling, for example the approach of membranes to each other, docking and even fusion. Such processes are essential for the repair of damaged cell envelopes or for the targeted release of membrane vesicles, which ensure the transport of substances across the membrane. “We can finally see how ferlins are really structured - it's like going from a blurred sketch to a razor-sharp portrait,” says Prof. Dr. Tobias Moser, director of the Institute of Auditory Neuroscience at the UMG and MBExC spokesperson.
The results have been published in the scientific journal “The EMBO Journal”.
Original publication:
Constantin Cretu, Aleksandar Chernev, Csaba Zoltan Kibedi Szabo, Vladimir Pena, Henning Urlaub, Tobias Moser, Julia Preobraschenski. Structural insights into lipid membrane binding by human ferlins. The EMBO Journal (2025). DOI: 10.1038/s44318-025-00463-8
Great potential for targeted treatment measures
The findings provide an important frame of reference for genetic diagnostics: many disease-relevant point mutations in the genome change the ferlin structure only slightly, but with serious consequences. “Now we can pinpoint exactly where these mutations affect - and what specific effects they have,” explains Dr. Constantin Cretu, head of the research group ‘Dynamics and Structure of ferlins’ at the Institute of Auditory Neuroscience at the UMG and Junior Fellow at the MBExC.
This discovery also has great potential for the development of modern therapies. The new structural knowledge enables the targeted design of functional mini-ferlines. These compact protein modules fit into viral vectors that serve as transport vehicles and thus pave the way for new therapies for muscle atrophy or hearing disorders. “This is molecular biology with engineering skills,” adds Dr. Julia Preobraschenski, head of the ‘Biochemistry of membrane dynamics’ working group at the Institute of Auditory Neuroscience at the UMG and Junior Fellow at the MBExC. “We don't just study proteins - we also consider how we can repair them.”
The significance of the findings extends beyond rare diseases: Myoferlin is produced in increased quantities in various types of tumors, where it helps cancer cells to grow and spread. For the first time, the new structure now provides starting points for the development of targeted drugs - such as small molecules that inhibit specific ferlin functions.
Prof. Dr. Tobias Moser,
Institute of Auditory Neuroscience,
Cluster of Excellence Multiscale Bioimaging (MBExC),
Collaborative Research Center 1690,
Phone 0551 / 39-63071,
tobias.moser@med.uni-goettingen.de
Constantin Cretu, Aleksandar Chernev, Csaba Zoltan Kibedi Szabo, Vladimir Pena, Henning Urlaub, Tobias Moser, Julia Preobraschenski. Structural insights into lipid membrane binding by human ferlins. The EMBO Journal (2025). DOI: 10.1038/s44318-025-00463-8
http://www.auditory-neuroscience.uni-goettingen.de - Institute of Auditory Neuroscience
https://mbexc.de/ - Cluster of Excellence “Multiscale Bioimaging” (MBExC)
Prof. Tobias Moser, director of the Institute of Auditory Neuroscience at the University Medical Cen ...
umg/frank stefan kimmel
Cryo-EM micrograph (left) of myoferlin particles (with one particle highlighted circle). 3D reconstr ...
constantin cretu/mbexc
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