There are two forms of otoferlin protein. The short form of the protein has three
C2 domains and a single
carboxy-terminal transmembrane domain found also in the
C. elegans spermatogenesis factor FER-1 and human
dysferlin. The long form has six C2 domains.
Dysferlin and
myoferlin are proteins found in humans that are
homologous to otoferlin. Both dysferlin and myoferlin have seven
C2 domains. A C2 domain is a
protein structural domain involved in targeting proteins to
cell membranes. C2A in otoferlin's longer form, with six C2 domains, is structurally similar to dysferlin C2A. However, loop 1 in the calcium (Ca2+) binding site of otoferlin C2A is significantly shorter than the homologous loop in dysferlin and myoferlin C2A domains. Therefore, it is unable to bind to calcium. Otoferlin C2A is also unable to bind to
phospholipids and hence it is structurally and functionally distinct from other C2 domains. Nonetheless, the
homology suggests that this protein may be involved in
vesicle membrane fusion. Similar to dysferlin and myoferlin, otoferlin has a FerA domain and its FerA domain has been shown to interact with
zwitterionic lipids in a calcium-dependent manner and with negatively charged lipids in a calcium-independent manner. The estimated charge of the FerA domain among ferlin proteins varies significantly. At pH 7, the estimated charge of dysferlin is -8.4 while otoferlin FerA is +8.5. Several
transcript variants encoding multiple
isoforms have been found for this gene. == Clinical significance ==