Structure and function of otoferlin, a synaptic protein of sensory hair cells essential for hearing.

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 si

SUBMITTER: Chen H 

PROVIDER: S-EPMC12526402 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature