9SE5
Mouse otoferlin (216-1931) in the lipid-free, Ca2+-bound state, "open" conformation (class 2)
Summary for 9SE5
| Entry DOI | 10.2210/pdb9se5/pdb |
| Related | 9QE2 |
| EMDB information | 53046 54802 |
| Descriptor | Otoferlin, CALCIUM ION (2 entities in total) |
| Functional Keywords | ferlins, otoferlin, multi-c2 domain, membrane protein |
| Biological source | Mus musculus (house mouse) |
| Total number of polymer chains | 1 |
| Total formula weight | 200618.00 |
| Authors | |
| Primary citation | Chen, H.,Cretu, C.,Trebilcock, A.,Evdokimova, N.,Babai, N.,Feldmann, L.,Leidner, F.,Benseler, F.,Mutschall, S.,Esch, K.,Szabo, C.Z.K.,Pena, V.,Pape, C.,Grubmuller, H.,Strenzke, N.,Brose, N.,Wichmann, C.,Preobraschenski, J.,Moser, T. Structure and function of otoferlin, a synaptic protein of sensory hair cells essential for hearing. Sci Adv, 11:eady8532-eady8532, 2025 Cited by PubMed 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-C domain protein otoferlin that is affected by human deafness mutations. Otoferlin is essential for IHC exocytosis, but how it binds Ca 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 CB-CG domains and repositions CF and CG domains. Disruption of Ca-binding sites of the CD domain in mice altered synaptic sound encoding and eliminated the Ca cooperativity of IHC exocytosis, indicating that it requires the binding of several Ca-ions by otoferlin. Together, our findings elucidate molecular mechanisms underlying otoferlin-mediated SV docking and support the role of otoferlin as Ca sensor of SV fusion in IHCs. PubMed: 41091875DOI: 10.1126/sciadv.ady8532 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.43 Å) |
Structure validation
Download full validation report
