Structure and function of otoferlin, a synaptic protein of sensory hair cells essential for hearing.
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Embargo End Date
ICR Authors
Authors
Chen, H
Cretu, C
Trebilcock, A
Evdokimova, N
Babai, N
Feldmann, L
Leidner, F
Benseler, F
Mutschall, S
Esch, K
Szabo, CZK
Pena, V
Pape, C
Grubmüller, H
Strenzke, N
Brose, N
Wichmann, C
Preobraschenski, J
Moser, T
Cretu, C
Trebilcock, A
Evdokimova, N
Babai, N
Feldmann, L
Leidner, F
Benseler, F
Mutschall, S
Esch, K
Szabo, CZK
Pena, V
Pape, C
Grubmüller, H
Strenzke, N
Brose, N
Wichmann, C
Preobraschenski, J
Moser, T
Document Type
Journal Article
Date
2025-10-17
Date Accepted
Abstract
Hearing relies upon speedy synaptic transmission of sound information from inner hair cells (IHCs) to spiral ganglion neurons. To accomplish this, IHCs use a sophisticated presynaptic machinery including the multi-C2 domain protein otoferlin that is affected by human deafness mutations. Otoferlin is essential for IHC exocytosis, but how it binds Ca2+ and the target membrane to serve synaptic vesicle (SV) tethering, docking, and fusion remained unclear. Here, we obtained cryo-electron microscopy structures of otoferlin and employed molecular dynamics simulations of membrane binding. We show that membrane binding by otoferlin involves C2B-C2G domains and repositions C2F and C2G domains. Disruption of Ca2+-binding sites of the C2D domain in mice altered synaptic sound encoding and eliminated the Ca2+ cooperativity of IHC exocytosis, indicating that it requires the binding of several Ca2+-ions by otoferlin. Together, our findings elucidate molecular mechanisms underlying otoferlin-mediated SV docking and support the role of otoferlin as Ca2+ sensor of SV fusion in IHCs.
Citation
Science Advances, 2025, 11 (42), pp. eady8532 -
Source Title
Science Advances
Publisher
AMER ASSOC ADVANCEMENT SCIENCE
ISSN
2375-2548
eISSN
2375-2548
Collections
Research Team
Mech of pre-mRNA splicing