Schematic illustration of otoferlin with a ring-shaped association of its particular person C2 domains (coloured on the left and proper) and transmembrane area (gentle blue) anchoring it within the synaptic vesicle (indicated as a grey semicircle). Via the interplay of otoferlin with the cell membrane (grey space on the backside of the picture), the synaptic vesicle “docks” onto the membrane and adjustments its construction (indicated by the coloured circles on the left and proper on the backside of the picture). This course of results in the fusion of the 2 membranes (indicated by the white circles on the backside middle of the picture). Credit score: UMG/Alexey Chizhik
Researchers in Göttingen, Germany, have elucidated the construction and performance of otoferlin, a protein that performs a vital function within the listening to course of. Lack of otoferlin or impairment of its perform causes a frequent type of congenital deafness. The outcomes, revealed within the journal Science Advances, mark a milestone after greater than twenty years of analysis on otoferlin at Göttingen Campus and contribute to optimizing the primary gene therapies for the therapy of deafness.
Listening to is a posh course of that’s nonetheless not totally understood. When a sound hits the ear, hair cells within the interior ear are mechanically activated. This causes a change in voltage within the cells, which ends up in the opening of calcium channels within the membrane. Calcium flows in and triggers the discharge of the neurotransmitter glutamate.
Throughout the hair cells, glutamate is transported in small vesicles to the purpose of contact between the hair cells and the auditory nerve cells, the so-called synapse. As soon as there, the vesicles connect themselves to the membrane of the hair cells and at last fuse with it on account of calcium binding to launch the glutamate. This prompts the opposing auditory nerve cells, which transmit the sound data to the mind.
Key molecule for listening to
The OTOF gene is chargeable for the formation of the protein otoferlin, which performs a vital function within the synaptic launch of glutamate. If otoferlin is lacking or its perform is impaired, sound data can’t be transmitted to the mind—a situation generally known as auditory synaptopathy, which is a frequent type of congenital deafness. How otoferlin influences this course of intimately had not but been totally elucidated.
Scientists on the College Medical Heart Göttingen (UMG), the Cluster of Excellence “Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells” (MBExC) and the brand new Collaborative Analysis Heart 1690 “Disease Mechanisms and Functional Restoration of Sensory and Motor Systems” have now succeeded in deciphering the construction and performance of otoferlin.
The outcomes present that otoferlin has a ring-shaped construction with a number of binding websites for calcium. The binding of calcium and membrane lipids results in a change within the otoferlin construction, on account of which the vesicle “docks” tightly to the membrane, thus getting ready for fusion. Otoferlin features as a calcium sensor for glutamate launch: if all binding websites of otoferlin are occupied by calcium, the vesicles fuse with the membrane, a course of through which different proteins are presumably concerned.
“This is a breakthrough in understanding the molecular basis of hearing. We now have a better understanding of how otoferlin works and how changes in the OTOF gene lead to protein malfunction,” says Prof. Dr. Tobias Moser, director of the Institute for Auditory Neuroscience at UMG, spokesperson for MBExC and SFB 1690, and final writer of the research.
“These new findings are not only fundamental to understanding auditory processing, but also highly relevant to clinical research: The first gene therapy for OTOF-related deafness has already been successfully tested in clinical trials. Detailed knowledge of the structure and function of otoferlin now opens up the possibility of optimizing these therapies in a targeted manner.”
The Göttingen crew used a mix of strategies for his or her investigations. Cryo-electron microscopy, or cryo-EM for brief, was used to look at the construction of otoferlin. To do that, the protein was flash-frozen in an answer after which examined in an electron microscope at -196°C. Hundreds of particular person photos of otoferlin had been taken below the microscope after which used to calculate a three-dimensional (3D) construction with assistance from high-performance computer systems.
Utilizing these high-resolution snapshots, the researchers had been in a position to visualize otoferlin for the primary time in near-atomic decision—each in its free type and in its type certain to synthetic membranes. This revealed that otoferlin kinds a ring-like construction that adjustments upon the binding of calcium and lipids and may actively deform the lipid membrane.
“With the high-resolution structure of otoferlin, we have made the molecular architecture of this unique hearing protein visible for the first time. We were able to see how certain areas of the protein, known as domains, move and interact to enable rapid signal transmission in the inner ear,” explains co-first writer Dr. Constantin Cretu, who carried out the structural biology analyses as a junior fellow of MBExC.
Molecular dynamics simulations in collaboration with researchers led by Prof. Dr. Helmut Grubmüller, director of the Division of Theoretical and Computational Biophysics on the Max Planck Institute for Multidisciplinary Sciences (MPI-NAT), subsequently confirmed that a number of C2 domains work together concurrently with the membrane, thereby enabling synaptic vesicles to dock and fuse.
In cooperation with Prof. Dr. Nils Brose, director of the Division of Molecular Neurobiology at MPI-NAT, it was demonstrated in an animal mannequin that focused adjustments in particular person calcium binding websites in otoferlin impaired synaptic sound encoding. Particularly, the disrupted calcium binding to otoferlin led to a discount within the likelihood of vesicle launch when the hair cells had been stimulated. A excessive likelihood of launch is a vital mechanism for high-precision sign transmission within the ear.
“The genetic mouse models have shown us how sensitive the system is to even the smallest changes. Even the failure of individual calcium binding sites led to deficits in the synaptic transmission of sound information—direct evidence of the central role of otoferlin as a calcium sensor for vesicle release,” provides first writer Han Chen, who performed a key function in advancing the evaluation of otoferlin perform within the mouse mannequin.
Extra data:
Han Chen et al, Construction and performance of otoferlin, a synaptic protein of sensory hair cells important for listening to, Science Advances (2025). DOI: 10.1126/sciadv.ady8532
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Detailed construction of key listening to protein factors solution to optimizing gene therapies for deafness (2025, October 16)
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