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
Journal
Sciende Advances
Citation
Sci Adv. 2025 Oct 17;11(42):eady8532.
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.
DOI
10.1126/sciadv.ady8532
Pubmed Link
