Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, Illinois 60637, USA.
J Biol Chem. 2011 Mar 4;286(9):7379-88. doi: 10.1074/jbc.M110.157222. Epub 2010 Dec 22.
The mammalian ferlins are calcium-sensing, C2 domain-containing proteins involved in vesicle trafficking. Myoferlin and dysferlin regulate myoblast fusion and muscle membrane resealing, respectively. Correspondingly, myoferlin is most highly expressed in singly nucleated myoblasts, whereas dysferlin expression is increased in mature, multinucleated myotubes. Myoferlin also mediates endocytic recycling and participates in trafficking the insulin-like growth factor receptor. We have now characterized a novel member of the ferlin family, Fer1L5, because of its high homology to dysferlin and myoferlin. We found that Fer1L5 protein is expressed in small myotubes that contain only two to four nuclei. We also found that Fer1L5 protein binds directly to the endocytic recycling proteins EHD1 and EHD2 and that the second C2 domain in Fer1L5 mediates this interaction. Reduction of EHD1 and/or EHD2 inhibits myoblast fusion, and EHD2 is required for normal translocation of Fer1L5 to the plasma membrane. The characterization of Fer1L5 and its interaction with EHD1 and EHD2 underscores the complex requirement of ferlin proteins and mediators of endocytic recycling for membrane trafficking events during myotube formation.
哺乳动物 ferlins 是一种钙感应、C2 结构域蛋白，参与囊泡运输。肌球蛋白和 dysferlin 分别调节成肌细胞融合和肌肉膜修复。相应地，肌球蛋白在单核成肌细胞中表达水平最高，而 dysferlin 的表达在成熟的多核肌管中增加。肌球蛋白还介导内体再循环，并参与胰岛素样生长因子受体的运输。由于其与 dysferlin 和肌球蛋白的高度同源性，我们现在对 ferlin 家族的一个新成员 Fer1L5 进行了特征描述。我们发现 Fer1L5 蛋白在仅包含两到四个核的小肌管中表达。我们还发现 Fer1L5 蛋白直接与内体再循环蛋白 EHD1 和 EHD2 结合，并且 Fer1L5 中的第二个 C2 结构域介导了这种相互作用。减少 EHD1 和/或 EHD2 会抑制成肌细胞融合，并且 EHD2 对于 Fer1L5 向质膜的正常易位是必需的。Fer1L5 的特征描述及其与 EHD1 和 EHD2 的相互作用突显了 ferlin 蛋白及其内体再循环介质在肌管形成过程中对膜运输事件的复杂要求。
