Dysferlin Binds SNAREs (Soluble N-Ethylmaleimide-sensitive Factor (NSF) Attachment Protein Receptors) and Stimulates Membrane Fusion in a Calcium-sensitive Manner
Dysferlin Binds SNAREs (Soluble N-Ethylmaleimide-sensitive Factor (NSF) Attachment Protein Receptors) and Stimulates Membrane Fusion in a Calcium-sensitive Manner
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DOI：
10.1074/jbc.m116.727016
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发表时间：
2016-07-08
影响因子：
4.8
通讯作者：
Johnson, Colin P.
中科院分区：
文献类型：
--
作者：
Codding, Sara J.;Marty, Naomi;Johnson, Colin P.
肌纤维肌膜撕裂的再密封是肌肉组织修复的必要步骤。最近的研究表明dysferlin在膜修复过程中起着关键作用，dysferlin的突变是肢带型肌营养不良症2B和Miyoshi肌病的原因。除了膜修复，dysferlin还与SNARE介导的胞吐事件有关，包括细胞因子释放和酸性鞘磷脂酶分泌。然而，目前尚不清楚dysferlin是否调节SNARE介导的膜融合。在这项研究中，我们证明了dysferlin与SNARE蛋白syntaxin 4和SNAP-23之间的直接相互作用。此外，FRET和体外重构脂质混合测定的分析表明，dysferlin以钙敏感的方式加速突触融合蛋白4/SNAP-23异二聚体形成和SNARE介导的脂质混合。这些结果支持dysferlin作为膜融合事件的钙敏感SNARE效应器的功能。
Resealing of tears in the sarcolemma of myofibers is a necessary step in the repair of muscle tissue. Recent work suggests a critical role for dysferlin in the membrane repair process and that mutations in dysferlin are responsible for limb girdle muscular dystrophy 2B and Miyoshi myopathy. Beyond membrane repair, dysferlin has been linked to SNARE-mediated exocytotic events including cytokine release and acid sphingomyelinase secretion. However, it is unclear whether dysferlin regulates SNARE-mediated membrane fusion. In this study we demonstrate a direct interaction between dysferlin and the SNARE proteins syntaxin 4 and SNAP-23. In addition, analysis of FRET and in vitro reconstituted lipid mixing assays indicate that dysferlin accelerates syntaxin 4/SNAP-23 heterodimer formation and SNARE-mediated lipid mixing in a calcium-sensitive manner. These results support a function for dysferlin as a calcium-sensing SNARE effector for membrane fusion events.