9SFL

Mouse otoferlin (residues 216-1931) in the lipid-bound state (merged datasets)

9SFL の概要

• エントリーDOI: 10.2210/pdb9sfl/pdb
• 関連するPDBエントリー: 9QE2 9SE5
• EMDBエントリー: 54827
• 分子名称: Otoferlin, CALCIUM ION, 1,2-DICAPROYL-SN-PHOSPHATIDYL-L-SERINE, ... (4 entities in total)
• 機能のキーワード: ferlins, otoferlin, multi-c2 domain, lipid nanodisc, membrane protein
• 由来する生物種: Mus musculus (house mouse)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 201689.18

構造登録者

Cretu, C.,Moser, T. (登録日: 2025-08-19, 公開日: 2025-11-05)

主引用文献

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

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: 41091875
DOI: 10.1126/sciadv.ady8532

実験手法

ELECTRON MICROSCOPY (2.27 Å)