Ca2+ binding to the C2E domain of otoferlin is required for hair cell exocytosis and hearing.

Dear Editor, Afferent synapses of cochlear inner hair cells(IHCs)employ a unique molecular machinery(see extended background in Supplementary Materials).Otoferlin is a key player in this machinery and its defects cause human auditory synaptopathy(Moser and Starr,2016).Otoferlin,a tail-anchored(Vogl et al.,2016)multi-C2-domain protein(Fig.1Ai)specific to hair cells(Roux et al.,2006),is a member of the ferlin protein fam-ily involved in membrane trafficking and repair that are of major disease relevance(Pangršič et al.,2012),also see Supplementary Materials.Otoferlin is distributed broadly within IHCs(Fig.2Aⅰ-Aⅲ;Pangrsic et al.,2010;Roux et al.,2006).